TWI567077B - Solid forms of (1r,4r)-6'-fluoro-n,n-dimethyl-4-phenyl-4',9'-dihydro-3'h-spiro-[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine hydrochloride - Google Patents

Solid forms of (1r,4r)-6'-fluoro-n,n-dimethyl-4-phenyl-4',9'-dihydro-3'h-spiro-[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine hydrochloride Download PDF

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TWI567077B
TWI567077B TW101146481A TW101146481A TWI567077B TW I567077 B TWI567077 B TW I567077B TW 101146481 A TW101146481 A TW 101146481A TW 101146481 A TW101146481 A TW 101146481A TW I567077 B TWI567077 B TW I567077B
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TW201331205A (en
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米歇爾 葛魯斯
史蒂芬 克魯格
安德烈亞斯 希伯
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歌林達有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Description

(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺-[環己烷-1,1’-吡喃並-[3,4,b]吲哚]-4-胺鹽酸鹽之固體形式 (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro-[cyclohexane-1,1'-pyridyl Solid form of carboxy-[3,4,b]吲哚]-4-amine hydrochloride

本發明涉及(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽之固體形式，特別是其晶形及/或非晶形，含此固體形式之醫藥組成物及藥劑，此類固體形式之用途以及獲得此類固體形式之方法。 The present invention relates to (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1' a solid form of pyrano[3,4,b]indole-4-amine hydrochloride, in particular crystalline form and/or amorphous form thereof, pharmaceutical composition and medicament containing the solid form, such solid form Uses and methods of obtaining such solid forms.

具藥理活性之藥劑可以不同之固體形式存在。例如，一種藥劑可以具有不同物理及化學特性之不同晶形存在。 The pharmacologically active agent may be present in different solid forms. For example, an agent may exist in different crystal forms having different physical and chemical properties.

不同物理性質可造成同一藥劑不同晶形之處理及存儲性能有極大差異。此類物理性質包括，例如熱力穩定性、結晶形態[形式、形狀、結構、粒子大小、粒子大小分布、結晶度、顏色]、波動行為、流動性、密度、容積比重、粉密度、表觀密度、振動密度、可耗竭性、可空性(emptyability)、硬性、可變形性、研磨性、可緊密性(compressability)、可壓縮性、脆度、伸縮性、熱量屬性[尤其係熔點]、可溶性[尤其係平衡溶解度、隨酸鹼值變化之可溶性]、溶出性[尤其係溶解率、特性溶出率]、復水性、吸水性、膠黏性、黏合性以及靜電充電度等類似性質。 Different physical properties can cause great differences in the processing and storage properties of different crystal forms of the same agent. Such physical properties include, for example, thermodynamic stability, crystalline morphology [form, shape, structure, particle size, particle size distribution, crystallinity, color], wave behavior, fluidity, density, bulk specific gravity, powder density, apparent density. , vibration density, exhaustibility, vacancy, hardness, deformability, abrasiveness, compressability, compressibility, brittleness, flexibility, thermal properties [especially melting point], solubility [Especially, the solubility is balanced, the solubility varies with the pH value], the dissolution properties (especially the dissolution rate, the characteristic dissolution rate), the rehydration, the water absorption, the adhesiveness, the adhesion, and the electrostatic chargeability.

此外，不同化學性質可造成同一藥劑不同晶形之性能屬性有極大差異。例如，吸水性極低之晶形(相對於其它晶形)可能具有更優越之化學穩定性及更長之儲放安定性(參見R.Hilfiker，同質異形體(Polymorphism)，2006 Wiley VCH，第235至242頁)。 In addition, different chemical properties can cause significant differences in the performance properties of different crystal forms of the same agent. For example, crystal forms with very low water absorption (relative to other crystal forms) may have superior chemical stability and longer storage stability (see R. Hilfiker, Polymorphism, 2006 Wiley VCH, page 235). 242 pages).

此外，一化合物之不同立體異構物可形成不同之晶形。於某些狀況下，可利用此差異將立體異構物相互分離。 In addition, different stereoisomers of a compound can form different crystal forms. In some cases, this difference can be utilized to separate stereoisomers from one another.

(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4b]吲哚]-4-胺為一特別受人關注之治療癌症(及其 它急性、內臟、神經病性及慢性疼痛等疼痛疾患)之藥物。此如通式(I)之藥劑之描述如下。 (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyran And [3,4b]吲哚]-4-amine is a particularly interesting treatment for cancer (and It is a drug for acute, visceral, neuropathic and chronic pain and other painful conditions. This description of the agent of the formula (I) is as follows.

迄今已知之(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4b]吲哚]-4-胺於各方面並不令人滿意，因此需要優越之固體形式。 (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1' The pyrano[3,4b]indole-4-amine is not satisfactory in all respects and therefore requires a superior solid form.

本發明之目的為提供優於先前技藝之形式或改質劑之(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺之形式或改質劑。 It is an object of the present invention to provide (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-- which is superior to prior art forms or modifiers. 3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine form or modifier.

本發明已達成此目的。 The present invention has achieved this object.

業已發現將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4b]吲哚]-4-胺轉化為鹽酸鹽，以其溶劑化物之形式較佳，可改善該化合物之水性溶解度。 It has been found that (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1' - Pyrano[3,4b]indole-4-amine is converted to the hydrochloride salt, preferably in the form of its solvate, which improves the aqueous solubility of the compound.

意外地發現將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4b]吲哚]-4-胺轉化為鹽酸鹽，選擇性地轉化為其溶劑化物之形式，及後續之結晶作用，可純化該化合物。 Unexpectedly found that (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1 The compound can be purified by conversion of '-pyrano[3,4b]indole]-4-amine to the hydrochloride salt, which is selectively converted to its solvate form, and subsequent crystallization.

此外，意外地發現可將不同晶形之(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4b]吲哚]-4-胺鹽酸 鹽，選擇性地於其溶劑化物之形式，製備為具有完全不同之性質。進步性晶形之描述如下。 Furthermore, it has been unexpectedly found that (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[ring] can be obtained in different crystal forms. Hexane-1,1'-pyrano[3,4b]indole-4-amine hydrochloride Salts, optionally in the form of their solvates, are prepared to have completely different properties. The description of the progressive crystal form is as follows.

根據通式(I)之化合物可系統性地分別稱為「1,1-(3-二甲胺基-3-苯基五亞甲基)-6-氟-1,3,4,9-四氫吡喃並[3,4-b]吲哚(反式)(1,1-(3-dime-thylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole(trans))」或「(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺((1r,4r)-6’-fluoro-N,N-dimethyl-4-phenyl-4’,9’-dihydro-3’H-spiro[cyclohexane-1,1’-pyrano[3,4,b]indol]-4-amine)」 The compounds according to formula (I) can be systematically referred to as "1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-, respectively. Tetrahydropyrano[3,4-b]indole (trans)(1,1-(3-dime-thylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3 , 4-b]indole(trans))" or "(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H- Spirulina [cyclohexane-1,1'-pyrano[3,4,b]indole]-4-amine ((1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl- 4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine)"

於根據本發明之固體形式中，根據通式(I)之化合物係以鹽酸鹽之形式存在。根據通式(I)化合物之鹽酸鹽於本文之定義包括鹽類、溶劑化物、共晶體、同素異形體、非晶形與多組份之複合物形式。為規範之目的，「鹽酸鹽(hydrochloride)」以指根據通式(I)之化合物係以氫氯酸-加成鹽較佳。根據通式(I)化合物之最基本功能基為N,N-二甲胺基基元，因此根據本發明，其以經質子化較佳。判定一化學物質是否以鹽類、共晶形、晶形或自由基等形式存在之方法，選擇性地於各情況中於其溶劑化物之形式，已為熟知此技術領域者所知，例如14N或15N固態核磁共振、X光繞射、紅外光光譜、示差掃描熱量分析、熱重分析、拉曼及X射線光電子光譜。於溶液中記錄到之1H-核磁共振亦可用於研究質子化是否存在。 In the solid form according to the invention, the compound according to formula (I) is present in the form of the hydrochloride salt. The hydrochloride salt of the compound of formula (I) as defined herein includes salts, solvates, co-crystals, allotropes, amorphous and multi-component complexes. For the purpose of specification, "hydrochloride" means that a compound according to formula (I) is preferably a hydrochloric acid-addition salt. The most basic functional group of the compound of the formula (I) is an N,N-dimethylamino group, and therefore it is preferred to be protonated according to the invention. A method for determining whether a chemical is present in the form of a salt, a eutectic form, a crystalline form or a free radical, etc., optionally in the form of its solvate in each case, is known to those skilled in the art, such as 14 N or 15 N solid state NMR, X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, Raman and X-ray photoelectron spectroscopy. The 1 H-NMR recorded in the solution can also be used to study the presence of protonation.

除非另有明確聲明，所有2Θ值係指利用波長為1.54060 Å之CuKα輻射，於23±3℃所測得之X射線繞射圖。 Unless otherwise expressly stated, all 2 Θ values refer to X-ray diffraction patterns measured at 23 ± 3 ° C using CuKα radiation at a wavelength of 1.54060 Å.

本發明其中一方面涉及(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4b]吲哚]-4-胺鹽酸鹽之固體形式。 One aspect of the invention relates to (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1 , a solid form of 1'-pyrano[3,4b]indole-4-amine hydrochloride.

根據本發明之固體形式可為晶形或非晶形，其可係非溶劑化物之 形式或溶劑化物之形式。 The solid form according to the invention may be crystalline or amorphous, which may be unsolvated Form or solvate form.

本發明之範疇亦包含晶形及/或非晶形混合物。 Also included within the scope of the invention are crystalline and/or amorphous mixtures.

於一較佳實施例中，其根據本發明之固體形式為非晶形。 In a preferred embodiment, the solid form according to the invention is amorphous.

適用於製備非晶形之方法已為熟知此技術領域者所知。例如，可採用下列方法獲得非晶形或非晶形混合物：i)由溶液中沉澱出，ii)冷凍乾燥，iii)噴霧乾燥，iv)熔融擠出，v)急驟蒸發，vi)焠火冷卻融化物，vii)於周圍溫度或於液態氮中研磨，及/或viii)採用毛細管結晶技術。 Suitable methods for preparing amorphous shapes are known to those skilled in the art. For example, an amorphous or amorphous mixture can be obtained by the following methods: i) precipitation from solution, ii) freeze drying, iii) spray drying, iv) melt extrusion, v) flash evaporation, vi) quenching to cool the melt, Vii) is ground at ambient temperature or in liquid nitrogen, and/or viii) using capillary crystallization techniques.

於一較佳實施例中，其根據本發明之固體形式為(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並-[3,4b]吲哚]-4-胺鹽酸鹽之晶形。 In a preferred embodiment, the solid form according to the invention is (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3 Crystal form of 'H-spiro[cyclohexane-1,1'-pyrano-[3,4b]indole]-4-amine hydrochloride.

於某些較佳實施例中，根據本發明之晶形具有一位於14.3±0.5(2Θ)之X光繞射波峰，及/或一位於17.1±0.5(2Θ)之X光繞射波峰，及/或一位於18.9±0.5(2Θ)之X光繞射波峰，及/或一位於19.6±0.5(2Θ)之X光繞射波峰。所有2Θ值係指使用波長為1.54060 Å之CuKα輻射所判定之X射線繞射圖。 In some preferred embodiments, the crystal form according to the present invention has an X-ray diffraction peak at 14.3 ± 0.5 (2 Θ), and/or an X-ray diffraction peak at 17.1 ± 0.5 (2 Θ), and / Or an X-ray diffraction peak at 18.9 ± 0.5 (2 Θ), and / or an X-ray diffraction peak at 19.6 ± 0.5 (2 Θ). All 2 Θ values refer to X-ray diffraction patterns determined using CuKα radiation at a wavelength of 1.54060 Å.

較佳地，該X光繞射波峰所顯示之相對強度為至少20%，以至少25%更佳，以至少30%又更佳，以至少40%再更佳，以至少45%最佳，以至少50%為首選。 Preferably, the X-ray diffraction peak exhibits a relative intensity of at least 20%, more preferably at least 25%, even more preferably at least 30%, even more preferably at least 40%, and most preferably at least 45%. At least 50% is preferred.

較佳地，根據本發明之晶形具有至少兩個選自由位於918±5 cm-1、1299±5 cm-1、1569±5 cm-1與1583±5 cm-1等拉曼波峰組成之群組。 Preferably, the crystal form according to the present invention has at least two groups selected from the group consisting of Raman peaks such as 918 ± 5 cm -1 , 1299 ± 5 cm -1 , 1569 ± 5 cm -1 and 1583 ± 5 cm -1 . group.

於一較佳實施例中，根據本發明之晶形具有至少三個選自由位於918±5 cm-1、1299±5 cm-1、1569±5 cm-1與1583±5 cm-1等拉曼波峰組成之群組。於一特佳實施例中，根據本發明之晶形具有全部四個波峰。 In a preferred embodiment, the crystal form according to the present invention has at least three selected from the group consisting of Raman at 918 ± 5 cm -1 , 1299 ± 5 cm -1 , 1569 ± 5 cm -1 and 1583 ± 5 cm -1 . A group of peaks. In a particularly preferred embodiment, the crystalline form according to the invention has all four peaks.

根據本發明之固體形式可為非溶劑化物或溶劑化物。因此，根據本發明之晶形可係一非溶劑化物或一溶劑化物。 The solid form according to the invention may be an unsolvate or a solvate. Thus, the crystalline form according to the invention may be an unsolvate or a solvate.

於一較佳實施例中，其晶形為一非溶劑化物。 In a preferred embodiment, the crystalline form is an asolvate.

於一較佳實施例中，其晶形不含任何溶劑化物。 In a preferred embodiment, the crystalline form does not contain any solvate.

於另一較佳實施例中，其非溶劑化物形式可含高達1.5重量百分比之水分。 In another preferred embodiment, the unsolvated form may contain up to 1.5 weight percent moisture.

於另一較佳實施例中，其非溶劑化物不含任何雜質。 In another preferred embodiment, the unsolvated material does not contain any impurities.

於本發明之意義，以將雜質解讀為用於合成根據通式(I)之化合物及/或合成其進步性固體形式之試劑或其分解產物較佳，或解讀為(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4b]吲哚]-4-胺或氫氯酸之分解產物或反應產物，或用於原位生成氫氯酸之試劑。 In the meaning of the present invention, it is preferred to interpret the impurity as an agent for synthesizing the compound according to formula (I) and/or synthesizing its progressive solid form or its decomposition product, or as (1r, 4r)-6 '-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4b]吲哚] 4-amine or a decomposition product or reaction product of hydrochloric acid, or an agent for in situ formation of hydrochloric acid.

於另一較佳實施例中，其晶形為溶劑化物。較佳地，該溶劑化物係選自由水合物、1,4-二氧陸圜之溶劑化物、啶之溶劑化物，或其混合物組成之群組。 In another preferred embodiment, the crystalline form is a solvate. Preferably, the solvate is selected from the group consisting of hydrates, solvates of 1,4-dioxane, solvates of pyridine, or mixtures thereof.

於一較佳實施例中，其溶劑化物形式不含任何雜質。 In a preferred embodiment, the solvate form is free of any impurities.

本發明另一方面涉及一種製備固體形式之方法，特別是根據本發明之晶形。 Another aspect of the invention relates to a process for the preparation of a solid form, in particular a crystalline form according to the invention.

於一較佳實施例中，其方法包括以下步驟：(a-1)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺之鹽酸鹽由自由鹼溶液或懸浮液中沉澱出。 In a preferred embodiment, the method comprises the steps of: (a-1) (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'- The hydrochloride salt of dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine is precipitated from a free base solution or suspension.

為規範之目的，「自由鹼(free base)」以指根據通式(I)之化合物非 以鹽之形式存在，尤其非以酸加成鹽之形式。 For the purposes of the specification, "free base" means a compound according to formula (I). It exists in the form of a salt, especially in the form of an acid addition salt.

可採用熟知此技術領域者已知之傳統溶媒做為此類溶液或懸浮液之溶媒，例如水或有機溶媒等選自由醇類，如甲醇、乙醇、正丙醇、異丙醇及正丁醇；酯類，如乙酸乙酯、乙酸正丙酯、乙酸異丙酯、乙酸正丁酯與乙酸異丁酯；酮類，如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；醚類，如甲基叔丁基醚、二***、四氫呋喃、二異丙醚與1,4-二氧陸圜；腈類，如乙腈；芳香族烴，如甲苯；飽和烴基，如正戊烷、正己烷與正庚烷；氯化烴，如二氯甲烷與三氯甲烷；及N-甲基-2-吡咯啶酮、二甲基甲醯胺、與二甲亞碸；及其混合物組成群組。 A conventional solvent known to those skilled in the art can be used as a solvent for such a solution or suspension, for example, water or an organic solvent or the like is selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol; Esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; ketones such as acetone, 2-butanone, pentan-2-one, pent-3-one , hexan-2-one and hexan-3-one; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, diisopropyl ether and 1,4-dioxane; nitriles such as acetonitrile; aromatic a hydrocarbon such as toluene; a saturated hydrocarbon group such as n-pentane, n-hexane and n-heptane; a chlorinated hydrocarbon such as dichloromethane and chloroform; and N-methyl-2-pyrrolidone, dimethyl Indoleamine, and dimethyl hydrazine; and mixtures thereof are grouped together.

可藉由添加氯化氫進行步驟(a-1)。 Step (a-1) can be carried out by adding hydrogen chloride.

於一較佳實施例中，所添加之氯化氫為氯化氫氣之形式。 In a preferred embodiment, the hydrogen chloride added is in the form of hydrogen chloride.

於另一較佳實施例中，氯化氫係藉由進行反應原位所生成，例如藉由於一水性溶液中添加三甲基氯矽烷。 In another preferred embodiment, hydrogen chloride is formed in situ by carrying out the reaction, for example by adding trimethylchlorodecane to an aqueous solution.

於又另一較佳實施例中，氯化氫為液體形式。 In yet another preferred embodiment, the hydrogen chloride is in liquid form.

於一較佳實施例中，其溶液為溶於水性溶媒之氯化氫，以氫氯酸特佳。 In a preferred embodiment, the solution is hydrogen chloride dissolved in an aqueous solvent, particularly preferably hydrochloric acid.

於另一較佳實施例中，其溶液為溶於有機溶媒之氯化氫溶液；以醇類，例如乙醇、異丙醇與正丁醇，及醚類，例如二***、二異丙醚、四氫呋喃、甲基四氫呋喃與1,4-二氧陸圜特佳。 In another preferred embodiment, the solution is a hydrogen chloride solution dissolved in an organic solvent; an alcohol such as ethanol, isopropanol and n-butanol, and an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, Methyltetrahydrofuran is particularly preferred with 1,4-dioxane.

較佳地，含氯化氫之溶液與自由鹼溶液含有相同溶媒。 Preferably, the hydrogen chloride containing solution contains the same solvent as the free base solution.

較佳地，該溶液所含之氯化氫濃度係介於0.01 mol/L至15 mol/L之範圍之間，以0.02 mol/L至12.5 mol/L之範圍更佳，以0.05 mol/L至10 mol/L之範圍又更佳，以0.1 mol/L至7.5 mol/L之範圍再更佳，以0.2 mol/L至10 mol/L之範圍最佳，以0.3 mol/L至5 mol/L之範圍為首選。 Preferably, the solution contains a concentration of hydrogen chloride in the range of 0.01 mol/L to 15 mol/L, more preferably in the range of 0.02 mol/L to 12.5 mol/L, and 0.05 mol/L to 10 The range of mol/L is better, preferably in the range of 0.1 mol/L to 7.5 mol/L, and preferably in the range of 0.2 mol/L to 10 mol/L, and 0.3 mol/L to 5 mol/L. The range is preferred.

較佳地，添加於該自由鹼溶液或懸浮液之氯化氫量為莫耳過剩量。 Preferably, the amount of hydrogen chloride added to the free base solution or suspension is a molar excess.

較佳地，於根據本發明之方法中，步驟(a-1)係於相應溶媒之沸點或較低之溫度中進行，以不高於80℃之溫度較佳，以不高於60℃又更佳，以不高於40℃再更佳，以20至40℃之溫度範圍為首選。 Preferably, in the method according to the present invention, the step (a-1) is carried out at a boiling point or a lower temperature of the corresponding solvent, preferably at a temperature not higher than 80 ° C, and not higher than 60 ° C. More preferably, it is more preferably not higher than 40 ° C, and the temperature range of 20 to 40 ° C is preferred.

較佳地，於根據本發明之方法中，於步驟(a-1)得到之懸浮液係經至少1分鐘之攪拌，以至少2分鐘較佳，以至少3分鐘更佳，以至少5分鐘又更佳，以至少10分鐘再更佳，以至少20分鐘最佳，以至少30分鐘為首選。 Preferably, in the method according to the present invention, the suspension obtained in the step (a-1) is stirred for at least 1 minute, preferably at least 2 minutes, more preferably at least 3 minutes, and at least 5 minutes. More preferably, it is preferably at least 10 minutes, preferably at least 20 minutes, and at least 30 minutes is preferred.

於一較佳實施例中，於步驟(a-1)得到之懸浮液係經至少1小時之攪拌，以至少4小時較佳，以至少6小時更佳，以至少12小時又更佳，以至少18小時再更佳，以至少1天最佳，以至少2天為首選。 In a preferred embodiment, the suspension obtained in the step (a-1) is stirred for at least 1 hour, preferably at least 4 hours, more preferably at least 6 hours, and even more preferably at least 12 hours. Better at least 18 hours, best for at least 1 day, and at least 2 days is preferred.

於另一較佳實施例中，於步驟(a-1)得到之懸浮液係經最久1天之攪拌，以最久12小時較佳，以最久6小時更佳，以最久2小時又更佳，以最久60分鐘再更佳，以最久45分鐘最佳，以最久30分鐘為首選。 In another preferred embodiment, the suspension obtained in the step (a-1) is stirred for a maximum of one day, preferably for a maximum of 12 hours, preferably for a maximum of 6 hours, and for a maximum of 2 hours. It is even better, with a maximum of 60 minutes and a better, with a maximum of 45 minutes, with a maximum of 30 minutes as the first choice.

較佳地，根據本發明之方法另包括以下步驟：(b-1)分離，以將於步驟(a-1)得到之固體過濾出較佳。 Preferably, the method according to the invention further comprises the step of: (b-1) separating, preferably filtering the solid obtained in step (a-1).

較佳地，根據本發明之方法另包括以下步驟：(c-1)將由步驟(b-1)得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (c-1) drying the solid obtained from step (b-1).

於一較佳實施例中，步驟(c-1)係於空氣、氮氣氣流或氬氣氣流中進行。 In a preferred embodiment, step (c-1) is carried out in a stream of air, nitrogen or argon.

於另一較佳實施例中，步驟(c-1)係於真空狀態進行，以0至900 mbar之真空狀態更佳，以1至500 mbar之真空狀態又更佳，以10至200 mbar之真空狀態特佳。 In another preferred embodiment, step (c-1) is carried out in a vacuum state, preferably in a vacuum of 0 to 900 mbar, more preferably in a vacuum of 1 to 500 mbar, and in a range of 10 to 200 mbar. The vacuum condition is particularly good.

較佳地，於根據本發明之方法中，步驟(c-1)係於介於0至60℃之溫度範圍中進行，以10至50℃較佳，以20至40℃更佳。 Preferably, in the method according to the present invention, the step (c-1) is carried out in a temperature range of from 0 to 60 ° C, preferably from 10 to 50 ° C, more preferably from 20 to 40 ° C.

於另一較佳實施例中，其方法包括以下步驟： (a-2)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]胺鹽酸鹽以一溶媒溶解。 In another preferred embodiment, the method includes the following steps: (a-2) (1r,4r)-6'-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1 , 1'-pyrano[3,4,b]indoleamine hydrochloride is dissolved in a solvent.

可採用熟知此技術領域者已知之傳統溶媒做為此類懸浮液之溶媒，特別是選自由醇類，例如甲醇、乙醇、正丙醇、異丙醇與正丁醇；酯類，例如乙酸乙酯、乙酸正丙酯、乙酸異丙酯、乙酸正丁酯與乙酸異丁酯；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；醚類，例如甲基叔丁基醚、二***、四氫呋喃、二異丙醚與1,4-二氧陸圜；腈類，例如乙腈；芳香族烴，例如甲苯；氯化烴，例如二氯甲烷與三氯甲烷；及N-甲基-2-吡咯啶酮、二甲基甲醯胺與二甲亞碸，及其混合物等有機溶媒組成之群組。飽和烴基，例如正戊烷、正己烷與正庚烷及水較不適用；(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽化合物於這些物質中僅有極低之溶解度。 Conventional solvents known to those skilled in the art can be employed as a solvent for such suspensions, particularly selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol; esters such as acetic acid B. Ester, n-propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; ketones such as acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one With hexanone; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, diisopropyl ether and 1,4-dioxane; nitriles such as acetonitrile; aromatic hydrocarbons such as toluene; A group of chlorinated hydrocarbons such as dichloromethane and chloroform; and an organic solvent such as N-methyl-2-pyrrolidone, dimethylformamide and dimethylhydrazine, and mixtures thereof. Saturated hydrocarbon groups such as n-pentane, n-hexane and n-heptane and water are less suitable; (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'- The dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride compound has only very low solubility in these materials.

較佳地，該溶媒係選自由二氯甲烷、N-甲基-2-吡咯啶酮、甲醇、二甲基甲醯胺及其混合物組成之群組。 Preferably, the solvent is selected from the group consisting of dichloromethane, N-methyl-2-pyrrolidone, methanol, dimethylformamide, and mixtures thereof.

於一特佳實施例中，其有機溶媒為二氯甲烷於甲醇之混合物。較佳地，二氯甲烷與甲醇之比例係介於10：1至1：10之範圍之間，以介於7：1至1：5之範圍之間更佳，以介於6：1至1：3之範圍之間又更佳，以介於5：1至1：1之範圍之間再更佳，以介於4：1至2：1之範圍之間最佳，以介於3.5：1至2.5：1之範圍之間為首選(體積/體積比)。 In a particularly preferred embodiment, the organic solvent is a mixture of dichloromethane and methanol. Preferably, the ratio of dichloromethane to methanol is between 10:1 and 1:10, more preferably between 7:1 and 1:5, and is between 6:1 and The range between 1:3 is even better, preferably between 5:1 and 1:1, preferably between 4:1 and 2:1, to between 3.5 : The range between 1 and 2.5:1 is preferred (volume/volume ratio).

較佳地，於根據本發明之方法中，步驟(a-2)係於相應溶媒或溶媒混合物之沸點或較低之溫度中進行，以不高於80℃之溫度更佳，以不高於60℃又更佳，以不高於40℃再更佳，以20至40℃之溫度範圍為首選。 Preferably, in the method according to the present invention, the step (a-2) is carried out at a boiling point or a lower temperature of the corresponding solvent or solvent mixture, preferably at a temperature not higher than 80 ° C, not higher than 60 ° C is more preferable, more preferably not higher than 40 ° C, and the temperature range of 20 to 40 ° C is preferred.

於一較佳實施例中，根據本發明之方法另包括以下步驟：(b-2)將於步驟(a-2)得到之溶液中之溶媒蒸發。 In a preferred embodiment, the method according to the invention further comprises the step of: (b-2) evaporating the solvent in the solution obtained in step (a-2).

適用於蒸發溶媒之方法已為熟知此技術領域者所知。較佳地，於根據本發明之方法中，溶媒係於空氣、空氣氣流或惰性氣體氣流中蒸發，特別是氬氣或氮氣氣流。然而，亦可於真空狀態蒸發溶媒，例如使用旋轉蒸發器。 Suitable methods for evaporating the solvent are known to those skilled in the art. Preferably, in the process according to the invention, the solvent is vaporized in a stream of air, air or inert gas, in particular an argon or nitrogen stream. However, it is also possible to evaporate the solvent in a vacuum state, for example using a rotary evaporator.

較佳地，於根據本發明之方法中，溶媒係於室溫蒸發。 Preferably, in the process according to the invention, the solvent is evaporated at room temperature.

於另一較佳實施例中，其方法另包括以下步驟：(b-2')將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽從由步驟(a-2)得到之溶液中沉澱出。 In another preferred embodiment, the method further comprises the step of: (b-2')-(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4', 9'-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride from the step (a-2) Precipitated in the solution.

適用之沉澱方法已為熟知此技術領域者所知。於根據本發明之方法中，可藉由降低由步驟(a-2)得到之溶液之體積及/或將該溶液冷卻進行步驟(b-2')，以冷卻至最高15℃之溫度較佳，以最高10℃更佳，以最高4至8℃最佳，及/或藉由將該溶液冷卻，以冷卻至較根據步驟(a-2)之溫度低至少10℃之溫度較佳，以至少低30℃更佳，以至少低60℃又更佳。 Suitable precipitation methods are known to those skilled in the art. In the method according to the present invention, it is preferred to cool to a temperature of up to 15 ° C by lowering the volume of the solution obtained in the step (a-2) and/or cooling the solution to carry out the step (b-2'). More preferably at a maximum of 10 ° C, preferably at a maximum of 4 to 8 ° C, and/or by cooling the solution to a temperature of at least 10 ° C lower than the temperature according to step (a-2), preferably It is preferably at least 30 ° C lower, and more preferably at least 60 ° C lower.

於一較佳實施例中，步驟(b-2')係藉由添加介質進行，於該介質中，(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並-[3,4,b]吲哚]-4-胺鹽酸鹽於步驟(a-2)得到之溶液中僅有極低之溶解度(「反溶劑(anti-solvent)」)。該介質以選自由酯類，如乙酸乙酯、乙酸正丙酯、乙酸異丙酯、乙酸正丁酯與乙酸異丁酯；醚類，例如於甲基叔丁基醚、二***與二異丙醚；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；腈類，例如乙腈；啶、乙酸與水組成之群組較佳。 In a preferred embodiment, step (b-2') is carried out by adding a medium in which (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl -4',9'-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano-[3,4,b]indole-4-amine hydrochloride in step (a -2) There is only a very low solubility ("anti-solvent") in the resulting solution. The medium is selected from the group consisting of esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; ethers such as methyl t-butyl ether, diethyl ether and diiso Propyl ether; ketones such as acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one and hexan-3-one; nitriles such as acetonitrile; pyridine, acetic acid and water The group is preferred.

對(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低溶解度之介質、沉澱劑或反溶劑之用量選擇，以可使溶解成分於添加後即開始沉澱較佳。 (1r,4r)-6'-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyridyl The argon [3,4,b]吲哚]-4-amine hydrochloride is selected only in the amount of a medium having a very low solubility, a precipitant or an anti-solvent, so that the dissolved component starts to precipitate immediately after the addition.

亦可將對(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低溶解度之介質之總量分成數個份量，以分成2或3個份量較佳。於此實施例中，溶解成分以於添加最後一份量後開始沉澱較佳。 (1r,4r)-6'-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1 The total amount of '-pyrano[3,4,b]吲哚]-4-amine hydrochloride which has only a very low solubility medium is divided into several parts, preferably divided into 2 or 3 parts. In this embodiment, it is preferred to dissolve the ingredients to initiate precipitation after the last amount is added.

溶解成分之沉澱反應，以添加沉澱劑後立即開始，以添加沉澱劑總量之後較佳，或者延遲2秒至120分鐘之後開始較佳。較佳地，溶解成分之沉澱反應以於最久90分鐘之期間內開始，以最久60分鐘內更佳，以最久30分鐘內又更佳，以最久5分鐘內再更佳，以最久60秒內最佳，以最久10秒內特佳。 The precipitation reaction of the dissolved components is started immediately after the addition of the precipitating agent, preferably after the total amount of the precipitating agent is added, or after a delay of 2 seconds to 120 minutes. Preferably, the precipitation reaction of the dissolved component starts within a period of up to 90 minutes, preferably in the longest 60 minutes, more preferably in the longest 30 minutes, and even better in the longest 5 minutes. The best in 60 seconds, the best in 10 seconds.

此外，對(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低溶解度之介質、沉澱劑或反溶劑用量之選擇方式，以於添加全部之反溶劑後90分鐘之期間內，溶解分成被完全地或至少高達90%之初始量被式沉澱出較佳，以最久80分鐘內更佳，以最久70分鐘內又更佳，以最久60分鐘內最佳。 Further, p-(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1' -pyrano[3,4,b]indole-4-amine hydrochloride is only available in a very low solubility medium, precipitant or anti-solvent in an amount of 90 minutes after the addition of all anti-solvents During the period, the dissolution fraction is preferably precipitated completely or at least as high as 90%, preferably in the longest 80 minutes, preferably in the longest 70 minutes, and the best in the longest 60 minutes. .

亦可藉由將於步驟(a-2)得到之溶液暴露於含溶媒之氣氛中進行步驟(b-2')，即利用蒸氣擴散結晶技術，於該溶液中，(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並-[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低之溶解度。 Step (b-2') may also be carried out by exposing the solution obtained in the step (a-2) to a solvent-containing atmosphere, that is, using a vapor diffusion crystallization technique, in the solution, (1r, 4r)-6 '-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano-[3,4, b] 吲哚]-4-amine hydrochloride has only very low solubility.

與此實施例中，以選擇二氯甲烷做為步驟(a-2)之溶媒較佳，及於步驟(a-2)得到之溶液以暴露於一含有己烷之周圍環境較佳。 In this embodiment, it is preferred to select dichloromethane as the solvent of the step (a-2), and the solution obtained in the step (a-2) is preferably exposed to a surrounding environment containing hexane.

較佳地，於根據本發明之方法中，步驟(b-2)或(b-2')後之所有步驟係係分別以介於40與0℃之間之溫度進行，以介於35與5℃之間更佳，以介於25與15℃之間又更佳。 Preferably, in the method according to the invention, all the steps after step (b-2) or (b-2') are carried out at a temperature between 40 and 0 ° C, respectively, to More preferably between 5 ° C and even better between 25 and 15 ° C.

較佳地，於根據本發明之方法中，於步驟(b-2')得到之懸浮液係經至少1分鐘之攪拌，以至少2分鐘較佳，以至少3分鐘更佳，以至少 5分鐘最佳。 Preferably, in the method according to the present invention, the suspension obtained in the step (b-2') is stirred for at least 1 minute, preferably at least 2 minutes, more preferably at least 3 minutes, at least 5 minutes best.

較佳地，根據本發明之方法另包括以下步驟：(c-2')分離，以將於步驟(b-2')得到之沉澱物過濾出較佳。 Preferably, the method according to the invention further comprises the step of: (c-2') separating, preferably filtering the precipitate obtained in step (b-2').

較佳地，根據本發明之方法另包括以下步驟：(d-2')將由步驟(c-2')得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (d-2') drying the solid obtained from step (c-2').

較佳地，於根據本發明之方法中，步驟(d-2')係於空氣或惰性氣體氣流中進行，例如氬氣或氮氣氣流。然而，取決於欲獲得之晶形，亦可於較高之溫度蒸發溶媒，例如，於20至60℃之溫度範圍。 Preferably, in the process according to the invention, step (d-2') is carried out in a stream of air or an inert gas, such as an argon or nitrogen stream. However, depending on the crystal form to be obtained, the solvent can also be evaporated at a higher temperature, for example, at a temperature ranging from 20 to 60 °C.

於又另一較佳實施例中，其方法包括以下步驟：(a-3)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽懸浮於一溶媒中。 In still another preferred embodiment, the method comprises the steps of: (a-3) (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9 '-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride was suspended in a solvent.

可採用熟知此技術領域者已知之溶媒做為此類懸浮液之溶媒，尤其是水或有機溶媒等選自由醇類，例如甲醇、乙醇、正丙醇、異丙醇與正丁醇；酯類，例如乙酸乙酯、乙酸正丙酯、乙酸異丙酯、乙酸正丁酯與乙酸異丁酯；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；醚類，例如甲基叔丁基醚、二***、四氫呋喃、二異丙醚與1,4-二氧陸圜；腈類，例如乙腈；芳香族烴，例如甲苯；飽和烴基，例如正戊烷、正己烷與正庚烷；氯化烴，例如二氯甲烷與三氯甲烷；及N-甲基-2-吡咯啶酮、二甲基甲醯胺與二甲亞碸；及其混合物組成之群組。 A solvent known to those skilled in the art can be used as a solvent for such a suspension, especially water or an organic solvent or the like selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol; For example, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; ketones such as acetone, 2-butanone, pentan-2-one, pentan-3-one, 2-ketone and hexan-3-one; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, diisopropyl ether and 1,4-dioxane; nitriles such as acetonitrile; aromatic hydrocarbons , for example, toluene; saturated hydrocarbon groups such as n-pentane, n-hexane and n-heptane; chlorinated hydrocarbons such as dichloromethane and chloroform; and N-methyl-2-pyrrolidone, dimethylformamide Group with dimethyl hydrazine; and mixtures thereof.

於一較佳實施例中，步驟(a-3)係於相應溶媒之沸點或較低之溫度中進行，以不高於100℃之溫度較佳，以不高於90℃更佳，以不高於80℃又更佳，以不高於60℃再更佳，以不高於40℃最佳，以15至35℃之溫度範圍為首選。 In a preferred embodiment, step (a-3) is carried out at a boiling point or a lower temperature of the corresponding solvent, preferably at a temperature not higher than 100 ° C, more preferably not higher than 90 ° C, or not It is more preferably higher than 80 ° C, more preferably not higher than 60 ° C, more preferably not higher than 40 ° C, and preferably in the temperature range of 15 to 35 ° C.

於另一較佳實施例中，步驟(a-3)係於100至40℃之溫度範圍中進行，以90至50℃更佳，以85至60℃最佳。 In another preferred embodiment, step (a-3) is carried out in a temperature range of from 100 to 40 ° C, more preferably from 90 to 50 ° C, and most preferably from 85 to 60 ° C.

較佳地，於根據本發明之方法中，於步驟(a-3)得到之懸浮液係經至少2小時之攪拌，以至少4小時較佳，以至少8小時更佳，以至少12小時又更佳，以至少16小時再更佳，以至少24小時最佳，以至少2天為首選。 Preferably, in the method according to the present invention, the suspension obtained in the step (a-3) is stirred for at least 2 hours, preferably at least 4 hours, more preferably at least 8 hours, and at least 12 hours. More preferably, at least 16 hours is better, at least 24 hours is best, and at least 2 days is preferred.

較佳地，根據本發明之方法另包括以下步驟：(b-3)分離，以將於步驟(a-3)得到之固體過濾出較佳。 Preferably, the method according to the invention further comprises the step of: (b-3) separating, preferably filtering the solid obtained in step (a-3).

較佳地，根據本發明之方法另包括以下步驟：(c-3)將於步驟(b-3)得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (c-3) drying the solid obtained in step (b-3).

於根據本發明之方法中，步驟(c-3)可於空氣或惰性氣體氣流中進行，例如氬氣或氮氣氣流。然而，可於真空狀態進行乾燥，以0至900 mbar之真空狀態更佳，以1至500 mbar之真空狀態又更佳，以10至200 mbar之真空狀態為首選。 In the process according to the invention, step (c-3) can be carried out in a stream of air or an inert gas, such as an argon or nitrogen stream. However, it is possible to dry in a vacuum state, preferably in a vacuum of 0 to 900 mbar, more preferably in a vacuum of 1 to 500 mbar, and preferably in a vacuum of 10 to 200 mbar.

較佳地，於根據本發明之方法中，步驟(c-3)係於介於0至60℃之溫度範圍中進行，以10至50℃較佳，以20至40℃更佳。 Preferably, in the method according to the present invention, the step (c-3) is carried out in a temperature range of from 0 to 60 ° C, preferably from 10 to 50 ° C, more preferably from 20 to 40 ° C.

本發明另一方面涉及一固體形式，以利用上述方法獲得之(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽之晶形較佳。 Another aspect of the invention relates to a solid form (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3 obtained by the above process The crystal form of 'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole]-4-amine hydrochloride is preferred.

下文中所有「晶形(crystalline form)」之引述係指(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽之晶形。 In the following, all references to "crystalline form" refer to (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H. - Crystal form of spiro [cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride.

本發明另一方面涉及晶形A。 Another aspect of the invention relates to Form A.

較佳地，根據本發明之晶形A具有一個或更多個選自由10.8±0.2(2Θ)、17.0±0.2(2Θ)、17.5±0.2(2Θ)、18.9±0.2(2Θ)與25.5±0.2(2Θ)等X光繞射波峰組成之群組。於數個實施例中，其晶形包含位於17.0±0.2(2Θ)、18.9±0.2(2Θ)與25.5±0.2(2Θ)之X光繞射波峰。於數個實施例中，其晶形包含一位於25.5±0.2(2Θ)之X光繞射波峰。 Preferably, the crystal form A according to the present invention has one or more selected from the group consisting of 10.8 ± 0.2 (2 Θ), 17.0 ± 0.2 (2 Θ), 17.5 ± 0.2 (2 Θ), 18.9 ± 0.2 (2 Θ) and 25.5 ± 0.2 ( 2Θ) A group of X-ray diffraction peaks. In several embodiments, the crystalline form comprises X-ray diffraction peaks at 17.0 ± 0.2 (2 Θ), 18.9 ± 0.2 (2 Θ), and 25.5 ± 0.2 (2 Θ). In several embodiments, the crystal form comprises an X-ray diffraction peak at 25.5 ± 0.2 (2 Å).

於數個較佳實施例中，晶形A包含位於10.8±0.2(2Θ)、17.0±0.2(2Θ)、18.9±0.2(2Θ)、25.5±0.2(2Θ)及選擇性地17.5±0.2(2Θ)之X光繞射波峰。 In several preferred embodiments, Form A comprises 10.8 ± 0.2 (2 Θ), 17.0 ± 0.2 (2 Θ), 18.9 ± 0.2 (2 Θ), 25.5 ± 0.2 (2 Θ), and optionally 17.5 ± 0.2 (2 Θ). X-ray diffraction peaks.

根據本發明之晶形A可額外具有至少一個選自由8.4±0.2(2Θ)、20.0±0.2(2Θ)、20.7±0.2(2Θ)、24.1±0.2(2Θ)、27.9±0.2(2Θ)、30.2±0.2(2Θ)、30.8±0.2(2Θ)與34.3±0.2(2Θ)等X光繞射波峰組成之群組。 The crystal form A according to the present invention may additionally have at least one selected from the group consisting of 8.4 ± 0.2 (2 Θ), 20.0 ± 0.2 (2 Θ), 20.7 ± 0.2 (2 Θ), 24.1 ± 0.2 (2 Θ), 27.9 ± 0.2 (2 Θ), 30.2 ± A group consisting of 0.2 (2 Θ), 30.8 ± 0.2 (2 Θ) and 34.3 ± 0.2 (2 Θ) X-ray diffraction peaks.

此外，根據本發明之晶形A之特徵亦可為其具有一個或更多個選自由10.8±0.2(2Θ)、17.0±0.2(2Θ)、17.5±0.2(2Θ)、18.9±0.2(2Θ)與25.5±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由8.4±0.2(2Θ)、20.0±0.2(2Θ)、20.7±0.2(2Θ)、24.1±0.2(2Θ)、27.9±0.2(2Θ)、30.2±0.2(2Θ)、30.8±0.2(2Θ)與34.3±0.2(2Θ)等X光繞射波峰組成之群組，其額外具有至少一個選自由21.6±0.2(2Θ)、22.3±0.2(2Θ)、23.6±0.2(2Θ)、26.3±0.2(2Θ)、28.4±0.2(2Θ)、33.7±0.2(2Θ)與34.6±0.2(2Θ)等X光繞射波峰組成之群組。 Further, the crystal form A according to the present invention may be characterized in that it has one or more selected from the group consisting of 10.8 ± 0.2 (2 Θ), 17.0 ± 0.2 (2 Θ), 17.5 ± 0.2 (2 Θ), and 18.9 ± 0.2 (2 Θ). a group consisting of 25.5 ± 0.2 (2 Θ) and other X-ray diffraction peaks, and optionally one or more selected from the group consisting of 8.4 ± 0.2 (2 Θ), 20.0 ± 0.2 (2 Θ), 20.7 ± 0.2 (2 Θ), 24.1 Groups of X-ray diffraction peaks such as ±0.2 (2Θ), 27.9±0.2 (2Θ), 30.2±0.2 (2Θ), 30.8±0.2 (2Θ), and 34.3±0.2(2Θ), which additionally have at least one selection Free 21.6 ± 0.2 (2 Θ), 22.3 ± 0.2 (2 Θ), 23.6 ± 0.2 (2 Θ), 26.3 ± 0.2 (2 Θ), 28.4 ± 0.2 (2 Θ), 33.7 ± 0.2 (2 Θ) and 34.6 ± 0.2 (2 Θ), etc. A group of X-ray diffraction peaks.

根據本發明之晶形A之特徵可為其另具有一個或更多個選自由10.8±0.2(2Θ)、17.0±0.2(2Θ)、17.5±0.2(2Θ)、18.9±0.2(2Θ)與25.5±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由8.4±0.2(2Θ)、20.0±0.2(2Θ)、20.7±0.2(2Θ)、24.1±0.2(2Θ)、27.9±0.2(2Θ)、30.2±0.2(2Θ)、30.8±0.2(2Θ)與34.3±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由21.6±0.2(2Θ)、22.3±0.2(2Θ)、23.6±0.2(2Θ)、26.3±0.2(2Θ)、28.4±0.2(2Θ)、33.7±0.2(2Θ)與34.6±0.2(2Θ)等X光繞射波峰組成之群組，其額外具有至少一個選自由12.3±0.2(2Θ)、13.1±0.2(2Θ)、22.6±0.2(2Θ)、23.3±0.2(2Θ)、26.8±0.2(2Θ)、29.2±0.2(2Θ)、31.5±0.2(2Θ)與32.4±0.2(2Θ)等X光繞射波峰組成之群組。 The crystal form A according to the present invention may be characterized in that it has one or more selected from the group consisting of 10.8 ± 0.2 (2 Θ), 17.0 ± 0.2 (2 Θ), 17.5 ± 0.2 (2 Θ), 18.9 ± 0.2 (2 Θ) and 25.5 ± a group consisting of 0.2 (2 Θ) and other X-ray diffraction peaks, and optionally one or more selected from the group consisting of 8.4 ± 0.2 (2 Θ), 20.0 ± 0.2 (2 Θ), 20.7 ± 0.2 (2 Θ), 24.1 ± 0.2 (2Θ), 27.9±0.2 (2Θ), 30.2±0.2 (2Θ), 30.8±0.2 (2Θ) and 34.3±0.2 (2Θ) and other groups of X-ray diffraction peaks, and optionally one or more Selected from 21.6±0.2(2Θ), 22.3±0.2(2Θ), 23.6±0.2(2Θ), 26.3±0.2(2Θ), 28.4±0.2(2Θ), 33.7±0.2(2Θ) and 34.6±0.2(2Θ) a group of X-ray diffraction peaks, the additional having at least one selected from the group consisting of 12.3 ± 0.2 (2 Θ), 13.1 ± 0.2 (2 Θ), 22.6 ± 0.2 (2 Θ), 23.3 ± 0.2 (2 Θ), 26.8 ± 0.2 Groups of X-ray diffraction peaks such as (2Θ), 29.2±0.2 (2Θ), 31.5±0.2 (2Θ), and 32.4±0.2 (2Θ).

所有2Θ值係指利用波長為1.54060 Å之CuKα輻射所測得之 X射線繞射圖。 All 2 Θ values are measured using CuKα radiation with a wavelength of 1.54060 Å. X-ray diffraction pattern.

於示差掃描熱量分析中，根據本發明之晶形A以具有一尖峰溫度為258至268℃之吸熱事件較佳，以259至267℃更佳，以260至266℃又更佳，以261至265℃再更佳，以262至265℃為首選。 In the differential scanning calorimetry, the crystal form A according to the present invention preferably has an endothermic event having a peak temperature of 258 to 268 ° C, more preferably 259 to 267 ° C, even more preferably 260 to 266 ° C, and 261 to 265. °C is even better, with 262 to 265 ° C as the first choice.

較佳地，根據本發明之晶形A進一步具有另一吸熱事件，以介於210至275℃之溫度範圍之間較佳。 Preferably, Form A according to the present invention further has another endothermic event, preferably between the temperature range of 210 to 275 °C.

根據本發明之晶形A之特徵可另為其具有一個或更多個選自由1003±2 cm-1、1554±2 cm-1、2958±2 cm-1與3071±2 cm-1等拉曼光譜帶組成之群組。 The crystal form A according to the present invention may further have one or more of Raman selected from the group consisting of 1003 ± 2 cm -1 , 1554 ± 2 cm -1 , 2958 ± 2 cm -1 and 3071 ± 2 cm -1 . A group of spectral bands.

根據本發明之晶形A之特徵可另為其具有一個或更多個選自由1003±2 cm-1、1554±2 cm-1、2958±2 cm-1與3071±2 cm-1等拉曼光譜帶組成之群組；及/或一個或更多個選自由691±2 cm-1、914±2 cm-1、926±2 cm-1、1034±2 cm-1、1156±2 cm-1、1295±2 cm-1、1316±2 cm-1、1372±2 cm-1、1441±2 cm-1、1470±2 cm-1、1582±2 cm-1、2882±2 cm-1、2907±2 cm-1、2935±2 cm-1、2986±2 cm-1、3020±2 cm-1與3041±2 cm-1等拉曼光譜帶組成之群組。 The crystal form A according to the present invention may further have one or more of Raman selected from the group consisting of 1003 ± 2 cm -1 , 1554 ± 2 cm -1 , 2958 ± 2 cm -1 and 3071 ± 2 cm -1 . a group of spectral bands; and/or one or more selected from the group consisting of 691 ± 2 cm -1 , 914 ± 2 cm -1 , 926 ± 2 cm -1 , 1034 ± 2 cm -1 , 1156 ± 2 cm - 1 , 1295 ± 2 cm -1 , 1316 ± 2 cm -1 , 1372 ± 2 cm -1 , 1441 ± 2 cm -1 , 1470 ± 2 cm -1 , 1582 ± 2 cm -1 , 2882 ± 2 cm -1 a group consisting of 2907 ± 2 cm -1 , 2935 ± 2 cm -1 , 2986 ± 2 cm -1 , 3020 ± 2 cm -1 and 3041 ± 2 cm -1 , such as Raman spectral bands.

根據本發明之晶形A之特徵可另為其具有一個或更多個選自由408±2 cm-1、451±2 cm-1、483±2 cm-1、512±2 cm-1、524±2 cm-1、536±2 cm-1、554±2 cm-1、597±2 cm-1、621±2 cm-1、642±2 cm-1、660±2 cm-1、712±2 cm-1、789±2 cm-1、824±2 cm-1、842±2 cm-1、869±2 cm-1、885±2 cm-1、965±2 cm-1、1049±2 cm-1、1061±2 cm-1、1095±2 cm-1、1112±2 cm-1、1128±2 cm-1、1175±2 cm-1、1201±2 cm-1、1208±2 cm-1、1234±2 cm-1、1268±2 cm-1、1353±2 cm-1、1600±2 cm-1、1625±2 cm-1、2542±2 cm-1、2811±2 cm-1、2847±2 cm-1、2858±2 cm-1與3201±2 cm-1等拉曼光譜帶組成之群組。 The crystal form A according to the present invention may further have one or more selected from the group consisting of 408±2 cm -1 , 451 ± 2 cm -1 , 483 ± 2 cm -1 , 512 ± 2 cm -1 , 524 ± 2 cm -1 , 536 ± 2 cm -1 , 554 ± 2 cm -1 , 597 ± 2 cm -1 , 621 ± 2 cm -1 , 642 ± 2 cm -1 , 660 ± 2 cm -1 , 712 ± 2 Cm -1 , 789 ± 2 cm -1 , 824 ± 2 cm -1 , 842 ± 2 cm -1 , 869 ± 2 cm -1 , 885 ± 2 cm -1 , 965 ± 2 cm -1 , 1049 ± 2 cm -1 , 1061 ± 2 cm -1 , 1095 ± 2 cm -1 , 1112 ± 2 cm -1 , 1128 ± 2 cm -1 , 1175 ± 2 cm -1 , 1201 ± 2 cm -1 , 1208 ± 2 cm - 1 , 1234 ± 2 cm -1 , 1268 ± 2 cm -1 , 1353 ± 2 cm -1 , 1600 ± 2 cm -1 , 1625 ± 2 cm -1 , 2542 ± 2 cm -1 , 2811 ± 2 cm -1 a group consisting of 2847±2 cm -1 , 2858±2 cm -1 and 3401 ± 2 cm -1 Raman spectral bands.

本發明另一方面涉及一種製備上述晶形A之方法。 Another aspect of the invention relates to a process for preparing the above Form A.

於一較佳實施例中，其方法包括以下步驟：(a-1)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺之鹽酸鹽由自由鹼溶液或懸浮液中沉澱出。 In a preferred embodiment, the method comprises the steps of: (a-1) (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'- The hydrochloride salt of dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine is precipitated from a free base solution or suspension.

可採用熟知此技術領域者已知之傳統溶媒做為此類溶液或懸浮液之溶媒，特別是水或有機溶媒等選自由醇類，例如甲醇、乙醇、正丙醇、異丙醇與正丁醇；酯類，例如乙酸乙酯、乙酸正丙酯、乙酸異丙酯、乙酸正丁酯與乙酸異丁酯；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；醚類，例如甲基叔丁基醚、二***、四氫呋喃、二異丙醚與1,4-二氧陸圜；腈類，例如乙腈；芳香族烴，例如甲苯；飽和烴基，例如正戊烷、正己烷與正庚烷；氯化烴，例如二氯甲烷與三氯甲烷；及N-甲基-2-吡咯啶酮、二甲基甲醯胺與二甲亞碸；及其混合物組成之群組。 A conventional solvent known to those skilled in the art can be used as a solvent for such a solution or suspension, and particularly water or an organic solvent or the like is selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol. ; esters, such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; ketones, such as acetone, 2-butanone, pentan-2-one, pent-3- Ketone, hexan-2-one and hexan-3-one; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, diisopropyl ether and 1,4-dioxane; nitriles such as acetonitrile; Aromatic hydrocarbons such as toluene; saturated hydrocarbon groups such as n-pentane, n-hexane and n-heptane; chlorinated hydrocarbons such as dichloromethane and chloroform; and N-methyl-2-pyrrolidone, dimethyl a group consisting of methotrexate and dimethyl hydrazine; and mixtures thereof.

較佳地，該溶媒係選自由醇類，例如甲醇、乙醇、正丙醇、異丙醇與正丁醇；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；醚類，例如甲基叔丁基醚、二***、四氫呋喃、二異丙醚與1,4-二氧陸圜；氯化烴，例如二氯甲烷與三氯甲烷；及其混合物組成之群組。 Preferably, the solvent is selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol; ketones such as acetone, 2-butanone, pentan-2-one, pent-3- Ketone, hexan-2-one and hexan-3-one; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, diisopropyl ether and 1,4-dioxane; chlorinated hydrocarbons, for example two a group consisting of methyl chloride and chloroform; and mixtures thereof.

特佳之溶媒係選自由四氫呋喃、1,4-二氧陸圜、丙酮、二氯甲烷、甲醇、乙醇、異丙醇、水或其混合物組成之群組，尤其係四氫呋喃/水，及丙酮/水之混合物。 A particularly preferred solvent is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, acetone, dichloromethane, methanol, ethanol, isopropanol, water or mixtures thereof, especially tetrahydrofuran/water, and acetone/water. a mixture.

可藉由添加氯化氫進行步驟(a-1)。 Step (a-1) can be carried out by adding hydrogen chloride.

於一較佳實施例中，所添加之氯化氫為氯化氫氣之形式。 In a preferred embodiment, the hydrogen chloride added is in the form of hydrogen chloride.

於另一較佳實施例中，氯化氫係藉由進行反應之方式原位生成，例如藉由於一水性溶液中添加三甲基氯矽烷。 In another preferred embodiment, hydrogen chloride is formed in situ by reaction, for example by the addition of trimethylchlorodecane to an aqueous solution.

於又另一較佳實施例中，氯化氫為液體形式。 In yet another preferred embodiment, the hydrogen chloride is in liquid form.

於一較佳實施例中，其溶液為溶於水性溶媒之氯化氫溶液，以氫氯酸特佳。 In a preferred embodiment, the solution is a hydrogen chloride solution dissolved in an aqueous solvent, particularly preferably hydrochloric acid.

於另一較佳實施例中，其溶液為一溶於有機溶媒之氯化氫溶液，以醇類，例如乙醇、異丙醇與正丁醇；及醚類，例如二***、二異***、四氫呋喃、甲基四氫呋喃與1,4-二氧陸圜為首選。 In another preferred embodiment, the solution is a hydrogen chloride solution dissolved in an organic solvent, such as alcohol, such as ethanol, isopropanol and n-butanol; and ethers such as diethyl ether, diisoethyl ether, tetrahydrofuran, Methyltetrahydrofuran and 1,4-dioxane are preferred.

較佳地，含氯化氫溶液與自由鹼溶液含有相同溶媒。 Preferably, the hydrogen chloride containing solution contains the same solvent as the free base solution.

較佳地，該溶液所含之氯化氫濃度係介於0.01 mol/L至15 mol/L之範圍之間，以0.02 mol/L至12.5 mol/L之範圍更佳，以0.05 mol/L至10 mol/L之範圍又更佳，以0.1 mol/L至7.5 mol/L之範圍再更佳，以0.2 mol/L至10 mol/L之範圍最佳，以0.3 mol/L至5 mol/L之範圍為首選。 Preferably, the solution contains a concentration of hydrogen chloride in the range of 0.01 mol/L to 15 mol/L, more preferably in the range of 0.02 mol/L to 12.5 mol/L, and 0.05 mol/L to 10 The range of mol/L is better, preferably in the range of 0.1 mol/L to 7.5 mol/L, and preferably in the range of 0.2 mol/L to 10 mol/L, and 0.3 mol/L to 5 mol/L. The range is preferred.

較佳地，添加於該自由鹼溶液或懸浮液之氯化氫量為莫耳過剩量。 Preferably, the amount of hydrogen chloride added to the free base solution or suspension is a molar excess.

較佳地，於根據本發明之方法中，步驟(a-1)係於相應溶媒之沸點或較低之溫度中進行，以不高於80℃較佳，以不高於60℃更佳，以不高於40℃又更佳，以20至40℃之溫度範圍為首選。 Preferably, in the method according to the present invention, the step (a-1) is carried out at a boiling point or a lower temperature of the corresponding solvent, preferably not higher than 80 ° C, more preferably not higher than 60 ° C, It is preferably not more than 40 ° C, and the temperature range of 20 to 40 ° C is preferred.

較佳地，於根據本發明之方法中，於步驟(a-1)得到之懸浮液係經至少1分鐘之攪拌，以至少2分鐘較佳，以至少3分鐘更佳，以至少5分鐘又更佳，以至少10分鐘再更佳，以至少20分鐘最佳，以至少30分鐘為首選。 Preferably, in the method according to the present invention, the suspension obtained in the step (a-1) is stirred for at least 1 minute, preferably at least 2 minutes, more preferably at least 3 minutes, and at least 5 minutes. More preferably, it is preferably at least 10 minutes, preferably at least 20 minutes, and at least 30 minutes is preferred.

於一較佳實施例中，於步驟(a-1)得到之懸浮液係經至少1小時之攪拌，以至少4小時較佳，以至少6小時更佳，以至少12小時又更佳，以至少18小時再更佳，以至少1天最佳，以至少2天為首選。 In a preferred embodiment, the suspension obtained in the step (a-1) is stirred for at least 1 hour, preferably at least 4 hours, more preferably at least 6 hours, and even more preferably at least 12 hours. Better at least 18 hours, best for at least 1 day, and at least 2 days is preferred.

於另一較佳實施例中，於步驟(a-1)得到之懸浮液係經最久1天之攪拌，以最久12小時較佳，以最久6小時更佳，以最久2小時又更佳，以最久60分鐘再更佳，以最久45分鐘最佳，以最久30分鐘為首選。 In another preferred embodiment, the suspension obtained in the step (a-1) is stirred for a maximum of one day, preferably for a maximum of 12 hours, preferably for a maximum of 6 hours, and for a maximum of 2 hours. It is even better, with a maximum of 60 minutes and a better, with a maximum of 45 minutes, with a maximum of 30 minutes as the first choice.

較佳地，根據本發明之方法另包括以下步驟： (b-1)分離，以將於步驟(a-1)得到之固體過濾出較佳。 Preferably, the method according to the invention further comprises the following steps: (b-1) Separation, preferably by filtering the solid obtained in the step (a-1).

較佳地，根據本發明之方法另包括以下步驟：(c-1)將由步驟(b-1)得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (c-1) drying the solid obtained from step (b-1).

於一較佳實施例中，步驟(c-1)係於空氣或惰性氣體氣流中進行，例如氬氣或氮氣氣流。 In a preferred embodiment, step (c-1) is carried out in a stream of air or an inert gas, such as an argon or nitrogen stream.

於另一較佳實施例中，步驟(c-1)係於真空狀態進行，以0至900 mbar之真空狀態更佳，以1至500 mbar之真空狀態又更佳，以10至200 mbar之真空狀態為首選。 In another preferred embodiment, step (c-1) is carried out in a vacuum state, preferably in a vacuum of 0 to 900 mbar, more preferably in a vacuum of 1 to 500 mbar, and in a range of 10 to 200 mbar. Vacuum is preferred.

較佳地，於根據本發明之方法中，步驟(c-1)係於0至60℃之溫度範圍中進行，以10至50℃較佳，以20至40℃更佳。 Preferably, in the method according to the present invention, the step (c-1) is carried out in a temperature range of from 0 to 60 ° C, preferably from 10 to 50 ° C, more preferably from 20 to 40 ° C.

於另一較佳實施例中，其方法包括以下步驟：(a-2)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽以一溶媒溶解。 In another preferred embodiment, the method comprises the steps of: (a-2) (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9' -Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride is dissolved in a solvent.

可採用熟知此技術領域者已知之傳統溶媒做為此類懸浮液之溶媒，特別是選自由醇類，例如甲醇、乙醇、正丙醇、異丙醇與正丁醇；酯類，例如乙酸乙酯、乙酸正丙酯、乙酸異丙酯、乙酸正丁酯與乙酸異丁酯；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；醚類，例如甲基叔丁基醚、二***、四氫呋喃、二異丙醚與1,4-二氧陸圜；腈類，例如乙腈；芳香族烴，例如甲苯；氯化烴，例如二氯甲烷與三氯甲烷；及N-甲基-2-吡咯啶酮、二甲基甲醯胺與二甲亞碸；及其混合物等有機溶媒組成之群組。飽和烴基，例如正戊烷、正己烷與正庚烷，及水較不適用，(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽化合物於這些物質中僅有極低之溶解度。 Conventional solvents known to those skilled in the art can be employed as a solvent for such suspensions, particularly selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol; esters such as acetic acid B. Ester, n-propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; ketones such as acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one With hexanone; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, diisopropyl ether and 1,4-dioxane; nitriles such as acetonitrile; aromatic hydrocarbons such as toluene; A group of chlorinated hydrocarbons, such as dichloromethane and chloroform; and N-methyl-2-pyrrolidone, dimethylformamide, and dimethylhydrazine; and mixtures thereof, such as organic solvents. Saturated hydrocarbon groups such as n-pentane, n-hexane and n-heptane, and water are less suitable, (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9' -Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride compound has only very low solubility in these materials .

較佳地，該溶媒係選自由二氯甲烷、N-甲基-2-吡咯啶酮、甲醇、二甲基甲醯胺及其混合物組成之群組。 Preferably, the solvent is selected from the group consisting of dichloromethane, N-methyl-2-pyrrolidone, methanol, dimethylformamide, and mixtures thereof.

於一特佳實施例中，其有機溶媒為二氯甲烷與甲醇之混合物。較佳地，二氯甲烷與甲醇之比例係介於10：1至1：10之範圍之間，以7：1至1：5之範圍更佳，以6：1至1：3之範圍又更佳，以5：1至1：1之範圍再更佳，以4：1至2：1之範圍最佳，以3.5：1至2.5：1之範圍為首選(體積/體積比)。 In a particularly preferred embodiment, the organic solvent is a mixture of dichloromethane and methanol. Preferably, the ratio of dichloromethane to methanol is between 10:1 and 1:10, more preferably in the range of 7:1 to 1:5, and in the range of 6:1 to 1:3. More preferably, it is preferably in the range of 5:1 to 1:1, preferably in the range of 4:1 to 2:1, and preferably in the range of 3.5:1 to 2.5:1 (volume/volume ratio).

較佳地，於根據本發明之方法中，步驟(a-2)係於相應溶媒之沸點或較低之溫度中進行，以不高於80℃較佳，以不高於60℃更佳，以不高於40℃又更佳，以20至40℃之溫度範圍為首選。 Preferably, in the method according to the present invention, the step (a-2) is carried out at a boiling point or a lower temperature of the corresponding solvent, preferably not higher than 80 ° C, more preferably not higher than 60 ° C, It is preferably not more than 40 ° C, and the temperature range of 20 to 40 ° C is preferred.

於一較佳實施例中，根據本發明之方法包括以下步驟：(b-2)將於步驟(a-2)得到之溶液中之溶媒蒸發。 In a preferred embodiment, the process according to the invention comprises the step of: (b-2) evaporating the solvent in the solution obtained in step (a-2).

適用於蒸發溶媒之方法已為熟知此技術領域者所知。較佳地，於根據本發明之方法中，溶媒係於空氣、空氣氣流或惰性氣體氣流中蒸發，特別是氬氣或氮氣氣流。然而，亦可於真空狀態蒸發溶媒，例如使用旋轉蒸發器。 Suitable methods for evaporating the solvent are known to those skilled in the art. Preferably, in the process according to the invention, the solvent is vaporized in a stream of air, air or inert gas, in particular an argon or nitrogen stream. However, it is also possible to evaporate the solvent in a vacuum state, for example using a rotary evaporator.

較佳地，於根據本發明之方法中，溶媒係於室溫蒸發。 Preferably, in the process according to the invention, the solvent is evaporated at room temperature.

於另一較佳實施例中，其方法另包括以下步驟：(b-2')將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽由從步驟(a-2)得到之溶液中沉澱出。 In another preferred embodiment, the method further comprises the step of: (b-2')-(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4', 9'-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride is obtained from step (a-2) Precipitated in the solution.

適用之沉澱方法已為熟知此技術領域者所知。於根據本發明之方法中，可藉由降低由步驟(a-2)得到之溶液之體積及/或將該溶液冷卻進行步驟(b-2')，以冷卻至最高15℃之溫度較佳，以最高10℃更佳，以最高4至8℃最佳，及/或藉由將該溶液冷卻，以冷卻至較根據步驟(a-2)之溫度低至少10℃之溫度較佳，以至少低30℃更佳，以至少低60℃又更佳。 Suitable precipitation methods are known to those skilled in the art. In the method according to the present invention, it is preferred to cool to a temperature of up to 15 ° C by lowering the volume of the solution obtained in the step (a-2) and/or cooling the solution to carry out the step (b-2'). More preferably at a maximum of 10 ° C, preferably at a maximum of 4 to 8 ° C, and/or by cooling the solution to a temperature of at least 10 ° C lower than the temperature according to step (a-2), preferably It is preferably at least 30 ° C lower, and more preferably at least 60 ° C lower.

於一較佳實施例中，步驟(b-2')係藉由添加介質進行，於該介 質中，(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並-[3,4,b]吲哚]-4-胺鹽酸鹽於步驟(a-2)得到之溶液中僅有極低之溶解度(「反溶劑(anti-solvent)」)。該介質以選自由酯類，如乙酸乙酯、乙酸正丙酯、乙酸異丙酯、乙酸正丁酯與乙酸異丁酯；醚類，例如於甲基叔丁基醚、二***與二異丙醚；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；腈類，例如乙腈；啶、乙酸與水組成之群組較佳。以乙酸、乙腈、丙酮與二***為首選。 In a preferred embodiment, step (b-2') is performed by adding a medium. Qualitative, (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1' -pyrano-[3,4,b]indole-4-amine hydrochloride has only very low solubility in the solution obtained in step (a-2) ("anti-solvent") . The medium is selected from the group consisting of esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; ethers such as methyl t-butyl ether, diethyl ether and diiso Propyl ether; ketones such as acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one and hexan-3-one; nitriles such as acetonitrile; pyridine, acetic acid and water The group is preferred. Acetic acid, acetonitrile, acetone and diethyl ether are preferred.

對(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低溶解度之介質、沉澱劑或反溶劑之用量選擇，以可使溶解成分於添加後即開始沉澱較佳。 (1r,4r)-6'-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyridyl The argon [3,4,b]吲哚]-4-amine hydrochloride is selected only in the amount of a medium having a very low solubility, a precipitant or an anti-solvent, so that the dissolved component starts to precipitate immediately after the addition.

亦可將對(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低溶解度之介質之總量分成數個份量，以分成2或3個份量較佳。於此實施例中，溶解成分以於添加最後一份量後開始沉澱較佳。 (1r,4r)-6'-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1 The total amount of '-pyrano[3,4,b]吲哚]-4-amine hydrochloride which has only a very low solubility medium is divided into several parts, preferably divided into 2 or 3 parts. In this embodiment, it is preferred to dissolve the ingredients to initiate precipitation after the last amount is added.

溶解成分之沉澱反應，以添加沉澱劑後立即開始，以添加沉澱劑總量之後較佳，或者延遲2秒至120分鐘之後開始。 The precipitation reaction of the dissolved components is started immediately after the addition of the precipitating agent, preferably after the total amount of the precipitating agent is added, or after a delay of 2 seconds to 120 minutes.

亦可藉由將於步驟(a-2)得到之溶液暴露於含溶媒之氣氛中進行步驟(b-2')，即利用蒸氣擴散結晶技術，於該溶液中(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低之溶解度。 Step (b-2') may also be carried out by exposing the solution obtained in the step (a-2) to a solvent-containing atmosphere, that is, using a vapor diffusion crystallization technique in the solution (1r, 4r)-6' -fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]吲哚]-4-amine hydrochloride has only very low solubility.

較佳地，於根據本發明之方法中，步驟(b-2)或(b-2')後之所有步驟係係分別以介於40與0℃之間之溫度進行，以介於35與5℃之間更佳，以介於25與15℃之間又更佳。 Preferably, in the method according to the invention, all the steps after step (b-2) or (b-2') are carried out at a temperature between 40 and 0 ° C, respectively, to More preferably between 5 ° C and even better between 25 and 15 ° C.

較佳地，於根據本發明之方法中，於步驟(b-2')得到之懸浮液係經至少1分鐘之攪拌，以至少2分鐘較佳，以至少3分鐘更佳，以至少 5分鐘最佳。 Preferably, in the method according to the present invention, the suspension obtained in the step (b-2') is stirred for at least 1 minute, preferably at least 2 minutes, more preferably at least 3 minutes, at least 5 minutes best.

較佳地，根據本發明之方法另包括以下步驟：(c-2')分離，以將於步驟(b-2')得到之沉澱物過濾出較佳。 Preferably, the method according to the invention further comprises the step of: (c-2') separating, preferably filtering the precipitate obtained in step (b-2').

較佳地，根據本發明之方法另包括以下步驟：(d-2')將由步驟(c-2')得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (d-2') drying the solid obtained from step (c-2').

較佳地，於根據本發明之方法中，步驟(d-2')係於空氣或惰性氣體氣流中進行，例如氬氣或氮氣氣流。 Preferably, in the process according to the invention, step (d-2') is carried out in a stream of air or an inert gas, such as an argon or nitrogen stream.

於又另一較佳實施例中，其方法包括以下步驟：(a-3)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽懸浮於一溶媒中。 In still another preferred embodiment, the method comprises the steps of: (a-3) (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9 '-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride was suspended in a solvent.

可採用熟知此技術領域者已知之傳統溶媒做為此類懸浮液之溶媒，特別是水與有機溶媒等選自由醇類，例如甲醇、乙醇、正丙醇、異丙醇與正丁醇；酯類，例如乙酸乙酯、乙酸正丙酯、乙酸異丙酯、乙酸正丁酯與乙酸異丁酯；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；醚類，例如甲基叔丁基醚、二***、四氫呋喃、二異丙醚與1,4-二氧陸圜；腈類，例如乙腈；芳香族烴，例如甲苯；飽和烴基，例如正戊烷、正己烷與正庚烷；氯化烴，例如二氯甲烷與三氯甲烷；及N-甲基-2-吡咯啶酮、二甲基甲醯胺與二甲亞碸；及其混合物組成之群組。. A conventional solvent known to those skilled in the art can be used as a solvent for such a suspension, and particularly water and an organic solvent or the like are selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol; And ketones such as acetone, 2-butanone, pentan-2-one, pentan-3-one, Hexan-2-one and hexan-3-one; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, diisopropyl ether and 1,4-dioxane; nitriles such as acetonitrile; aromatic a hydrocarbon such as toluene; a saturated hydrocarbon group such as n-pentane, n-hexane and n-heptane; a chlorinated hydrocarbon such as dichloromethane and chloroform; and N-methyl-2-pyrrolidone, dimethylformamidine a group of amines and dimethyl hydrazine; and mixtures thereof. .

較佳地，該溶媒為水。 Preferably, the solvent is water.

較佳地，於根據本發明之方法中，步驟(a-3)係於相應溶媒之沸點或較低溫度中進行，以不高於80℃之溫度較佳，以不高於60℃更佳，以不高於40℃又更佳，以15至35℃之溫度範圍為首選。 Preferably, in the method according to the present invention, the step (a-3) is carried out at a boiling point or a lower temperature of the corresponding solvent, preferably at a temperature not higher than 80 ° C, more preferably not higher than 60 ° C. It is preferably not more than 40 ° C, and the temperature range of 15 to 35 ° C is preferred.

較佳地，於根據本發明之方法中，由步驟(a-3)得到之懸浮液係經至少2小時之攪拌，以至少4小時較佳，以至少8小時更佳，以至少12小時又更佳，以至少16小時再更佳，以至少24小時最佳，以至少 2天為首選。 Preferably, in the method according to the present invention, the suspension obtained in the step (a-3) is stirred for at least 2 hours, preferably at least 4 hours, more preferably at least 8 hours, and at least 12 hours. Better, at least 16 hours is better, at least 24 hours is best, at least 2 days is preferred.

較佳地，根據本發明之方法另包括以下步驟：(b-3)分離，已將於步驟(a-3)得到之固體過濾出較佳。 Preferably, the method according to the invention further comprises the step of: (b-3) separating, the solid which has been obtained in step (a-3) is preferably filtered.

較佳地，根據本發明之方法另包括以下步驟：(c-3)將於步驟(b-3)得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (c-3) drying the solid obtained in step (b-3).

於根據本發明之方法中，步驟(c-3)可於空氣或惰性氣體氣流中進行，例如氬氣或氮氣氣流。然而，於真空狀態進行乾燥較佳，以0至900 mbar之真空狀態更佳，以1至500 mbar之真空狀態又更佳，以10至200 mbar之真空狀態為首選。 In the process according to the invention, step (c-3) can be carried out in a stream of air or an inert gas, such as an argon or nitrogen stream. However, it is preferred to carry out the drying in a vacuum state, preferably in a vacuum of 0 to 900 mbar, more preferably in a vacuum of 1 to 500 mbar, and preferably in a vacuum of 10 to 200 mbar.

較佳地，於根據本發明之方法中，步驟(c-3)係於0至60℃之溫度範圍中進行，以10至50℃較佳，以20至40℃更佳。 Preferably, in the method according to the present invention, the step (c-3) is carried out in a temperature range of from 0 to 60 ° C, preferably from 10 to 50 ° C, more preferably from 20 to 40 ° C.

本發明另一方面涉及利用上述方法獲得之晶形A。 Another aspect of the invention relates to Form A obtained by the above method.

本發明另一方面涉及晶形B。 Another aspect of the invention relates to Form B.

較佳地，根據本發明之晶形B具有一個或更多個選自由10.6±0.2(2Θ)、17.2±0.2(2Θ)、18.6±0.2(2Θ)、19.3±0.2(2Θ)、22.2±0.2(2Θ)、26.7±0.2(2Θ)與29.3±0.2(2Θ)等X光繞射波峰組成之群組。於數個較佳實施例中，其晶形包含位於18.6±0.2(2Θ)與19.3±0.2(2Θ)之X光繞射波峰。於數個較佳實施例中，其晶形包含一位於18.6±0.2(2Θ)之X光繞射波峰。 Preferably, the crystalline form B according to the present invention has one or more selected from the group consisting of 10.6 ± 0.2 (2 Θ), 17.2 ± 0.2 (2 Θ), 18.6 ± 0.2 (2 Θ), 19.3 ± 0.2 (2 Θ), 22.2 ± 0.2 ( 2Θ), 26.7±0.2 (2Θ) and 29.3±0.2 (2Θ) and other groups of X-ray diffraction peaks. In several preferred embodiments, the crystalline form comprises X-ray diffraction peaks at 18.6 ± 0.2 (2 Å) and 19.3 ± 0.2 (2 Å). In several preferred embodiments, the crystal form comprises an X-ray diffraction peak at 18.6 ± 0.2 (2 Å).

於數個較佳實施例中，晶形B包含位於10.6±0.2(2Θ)、17.2±0.2(2Θ)、18.6±0.2(2Θ)、19.3±0.2(2Θ)、26.7±0.2(2Θ)、29.3±0.2(2Θ)，及選擇性地位於22.2±0.2(2Θ)之X光繞射波峰。 In several preferred embodiments, Form B comprises 10.6 ± 0.2 (2 Θ), 17.2 ± 0.2 (2 Θ), 18.6 ± 0.2 (2 Θ), 19.3 ± 0.2 (2 Θ), 26.7 ± 0.2 (2 Θ), 29.3 ± 0.2 (2 Θ), and an X-ray diffraction peak selectively located at 22.2 ± 0.2 (2 Θ).

根據本發明之晶形B可額外具有至少一個選自由16.9±0.2(2Θ)、21.2±0.2(2Θ)、24.4±0.2(2Θ)、28.6±0.2(2Θ)、28.8±0.2(2Θ)、30.0±0.2(2Θ)、31.2±0.2(2Θ)與31.7±0.2(2Θ)等X光繞射波峰組成之群組。 The crystal form B according to the present invention may additionally have at least one selected from the group consisting of 16.9 ± 0.2 (2 Θ), 21.2 ± 0.2 (2 Θ), 24.4 ± 0.2 (2 Θ), 28.6 ± 0.2 (2 Θ), 28.8 ± 0.2 (2 Θ), 30.0 ± A group consisting of 0.2 (2 Θ), 31.2 ± 0.2 (2 Θ) and 31.7 ± 0.2 (2 Θ) X-ray diffraction peaks.

此外，根據本發明之晶形B之特徵可為其額外具有一個或更多個 選自由10.6±0.2(2Θ)、17.2±0.2(2Θ)、18.6±0.2(2Θ)、19.3±0.2(2Θ)、22.2±0.2(2Θ)、26.7±0.2(2Θ)與29.3±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由16.9±0.2(2Θ)、21.2±0.2(2Θ)、24.4±0.2(2Θ)、28.6±0.2(2Θ)、28.8±0.2(2Θ)、30.0±0.2(2Θ)、31.2±0.2(2Θ)與31.7±0.2(2Θ)等X光繞射波峰組成之群組，其額外具有至少一個選自由8.4±0.2(2Θ)、11.4±0.2(2Θ)、12.5±0.2(2Θ)、15.5±0.2(2Θ)、20.7±0.2(2Θ)、21.4±0.2(2Θ)、25.4±0.2(2Θ)、27.9±0.2(2Θ)與30.7±0.2(2Θ)等X光繞射波峰組成之群組。 Further, the feature of the crystal form B according to the present invention may have one or more additional thereto Free choice is 10.6±0.2(2Θ), 17.2±0.2(2Θ), 18.6±0.2(2Θ), 19.3±0.2(2Θ), 22.2±0.2(2Θ), 26.7±0.2(2Θ) and 29.3±0.2(2Θ) a group of X-ray diffraction peaks, and optionally one or more selected from the group consisting of 16.9 ± 0.2 (2 Θ), 21.2 ± 0.2 (2 Θ), 24.4 ± 0.2 (2 Θ), 28.6 ± 0.2 (2 Θ), a group consisting of X-ray diffraction peaks such as 28.8 ± 0.2 (2 Θ), 30.0 ± 0.2 (2 Θ), 31.2 ± 0.2 (2 Θ), and 31.7 ± 0.2 (2 Θ), which additionally have at least one selected from the group consisting of 8.4 ± 0.2 (2 Θ ), 11.4 ± 0.2 (2 Θ), 12.5 ± 0.2 (2 Θ), 15.5 ± 0.2 (2 Θ), 20.7 ± 0.2 (2 Θ), 21.4 ± 0.2 (2 Θ), 25.4 ± 0.2 (2 Θ), 27.9 ± 0.2 (2 Θ) A group consisting of X-ray diffraction peaks such as 30.7±0.2 (2Θ).

根據本發明之晶形B之特徵可進一步為其具有一個或更多個選自由10.6±0.2(2Θ)、17.2±0.2(2Θ)、18.6±0.2(2Θ)、19.3±0.2(2Θ)、22.2±0.2(2Θ)、26.7±0.2(2Θ)與29.3±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由16.9±0.2(2Θ)、21.2±0.2(2Θ)、24.4±0.2(2Θ)、28.6±0.2(2Θ)、28.8±0.2(2Θ)、30.0±0.2(2Θ)、31.2±0.2(2Θ)與31.7±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由8.4±0.2(2Θ)、11.4±0.2(2Θ)、12.5±0.2(2Θ)、15.5±0.2(2Θ)、20.7±0.2(2Θ)、21.4±0.2(2Θ)、25.4±0.2(2Θ)、27.9±0.2(2Θ)與30.7±0.2(2Θ)等X光繞射波峰組成之群組，其額外具有至少一個選自由14.2±0.2(2Θ)、27.1±0.2(2Θ)、28.3±0.2(2Θ)、32.9±0.2(2Θ)、33.4±0.2(2Θ)、33.8±0.2(2Θ)與34.7±0.2(2Θ)等X光繞射波峰組成之群組。 The crystal form B according to the present invention may further have one or more selected from the group consisting of 10.6 ± 0.2 (2 Θ), 17.2 ± 0.2 (2 Θ), 18.6 ± 0.2 (2 Θ), 19.3 ± 0.2 (2 Θ), 22.2 ± Groups of X-ray diffraction peaks such as 0.2 (2 Θ), 26.7 ± 0.2 (2 Θ), and 29.3 ± 0.2 (2 Θ), and optionally one or more selected from 16.9 ± 0.2 (2 Θ), 21.2 ± 0.2 X-ray diffraction such as (2Θ), 24.4±0.2 (2Θ), 28.6±0.2 (2Θ), 28.8±0.2 (2Θ), 30.0±0.2 (2Θ), 31.2±0.2 (2Θ) and 31.7±0.2(2Θ) The group of peaks, and optionally one or more selected from the group consisting of 8.4 ± 0.2 (2 Θ), 11.4 ± 0.2 (2 Θ), 12.5 ± 0.2 (2 Θ), 15.5 ± 0.2 (2 Θ), 20.7 ± 0.2 (2 Θ a group of X-ray diffraction peaks such as 21.4 ± 0.2 (2 Θ), 25.4 ± 0.2 (2 Θ), 27.9 ± 0.2 (2 Θ), and 30.7 ± 0.2 (2 Θ), which additionally have at least one selected from the group consisting of 14.2 ± 0.2 X-ray diffraction such as (2Θ), 27.1±0.2 (2Θ), 28.3±0.2 (2Θ), 32.9±0.2 (2Θ), 33.4±0.2 (2Θ), 33.8±0.2 (2Θ) and 34.7±0.2(2Θ) A group of peaks.

所有2Θ值係指利用波長為1.54060 Å之CuKα輻射所測得之X射線繞射圖。 All 2 Θ values refer to X-ray diffraction patterns measured using CuKα radiation at a wavelength of 1.54060 Å.

於示差掃描熱量分析中，根據本發明之晶形B以具有一尖峰溫度為261至271℃之吸熱事件較佳，以262至270℃更佳，以263至269℃又更佳，以264至268℃再更佳，以265至268℃為首選。 In the differential scanning calorimetry, the crystal form B according to the present invention preferably has an endothermic event having a peak temperature of 261 to 271 ° C, more preferably 262 to 270 ° C, even more preferably 263 to 269 ° C, and 264 to 268. °C is even better, with 265 to 268 ° C as the first choice.

較佳地，根據本發明之晶形A進一步具有另一放熱事件，其溫度 範完以介於210至265℃之間較佳。 Preferably, the crystal form A according to the present invention further has another exothermic event, the temperature thereof Preferably, the range is between 210 and 265 ° C.

根據本發明之晶形B之特徵可進一步為其具有一個或更多個選自由1300±2 cm-1、1569±2 cm-1、1583±2 cm-1與2992±2 cm-1等拉曼光譜帶組成之群組。 The crystal form B according to the present invention may further have one or more of Raman selected from the group consisting of 1300±2 cm -1 , 1569±2 cm -1 , 1583±2 cm -1 and 2992±2 cm -1 . A group of spectral bands.

根據本發明之晶形B之特徵可其另具有一個或更多個選自由1300±2 cm-1、1569±2 cm-1、1583±2 cm-1與2992±2 cm-1等拉曼光譜帶組成之群組；及/或一個或更多個選自由183±2 cm-1、919±2 cm-1、1001±2 cm-1、3054±2 cm-1與3069±2 cm-1等拉曼光譜帶組成之群組；及/或一個或更多個選自由160±2 cm-1、208±2 cm-1、491±2 cm-1、683±2 cm-1、1120±2 cm-1、1374±2 cm-1、1436±2 cm-1、1463±2 cm-1、1481±2 cm-1、2870±2 cm-1、2906±2 cm-1、2922±2 cm-1、2931±2 cm-1、2958±2 cm-1與3034±2 cm-1等拉曼光譜帶組成之群組。 The crystal form B according to the present invention may further have one or more Raman spectra selected from the group consisting of 1300 ± 2 cm -1 , 1569 ± 2 cm -1 , 1583 ± 2 cm -1 and 2992 ± 2 cm -1 . a group of constituents; and/or one or more selected from the group consisting of 183 ± 2 cm -1 , 919 ± 2 cm -1 , 1001 ± 2 cm -1 , 3054 ± 2 cm -1 and 3069 ± 2 cm -1 a group of equal Raman spectral bands; and/or one or more selected from the group consisting of 160 ± 2 cm -1 , 208 ± 2 cm -1 , 491 ± 2 cm -1 , 683 ± 2 cm -1 , 1120 ± 2 cm -1 , 1374 ± 2 cm -1 , 1436 ± 2 cm -1 , 1463 ± 2 cm -1 , 1481 ± 2 cm -1 , 2870 ± 2 cm -1 , 2906 ± 2 cm -1 , 2922 ± 2 A group consisting of a Raman spectral band such as cm -1 , 2931 ± 2 cm -1 , 2958 ± 2 cm -1 and 3034 ± 2 cm -1 .

根據本發明之晶形B之特徵可進一步為其具有一個或更多個選自由255±2 cm-1、279±2 cm-1、371±2 cm-1、397±2 cm-1、430±2 cm-1、450±2 cm-1、466±2 cm-1、518±2 cm-1、540±2 cm-1、557±2 cm-1、568±2 cm-1、598±2 cm-1、606±2 cm-1、620±2 cm-1、628±2 cm-1、710±2 cm-1、768±2 cm-1、786±2 cm-1、808±2 cm-1、820±2 cm-1、828±2 cm-1、856±2 cm-1、873±2 cm-1、888±2 cm-1、928±2 cm-1、957±2 cm-1、984±2 cm-1、1028±2 cm-1、1035±2 cm-1、1047±2 cm-1、1073±2 cm-1、1136±2 cm-1、1174±2 cm-1、1199±2 cm-1、1216±2 cm-1 1222±2 cm-1 1265±2 cm-1、1352±2 cm-1、1628±2 cm-1與2845±2 cm-1等拉曼光譜帶組成之群組。 The crystal form B according to the present invention may further have one or more selected from the group consisting of 255 ± 2 cm -1 , 279 ± 2 cm -1 , 371 ± 2 cm -1 , 397 ± 2 cm -1 , 430 ± 2 cm -1 , 450 ± 2 cm -1 , 466 ± 2 cm -1 , 518 ± 2 cm -1 , 540 ± 2 cm -1 , 557 ± 2 cm -1 , 568 ± 2 cm -1 , 598 ± 2 Cm -1 , 606 ± 2 cm -1 , 620 ± 2 cm -1 , 628 ± 2 cm -1 , 710 ± 2 cm -1 , 768 ± 2 cm -1 , 786 ± 2 cm -1 , 808 ± 2 cm -1 820 ± 2 cm -1 , 828 ± 2 cm -1 , 856 ± 2 cm -1 , 873 ± 2 cm -1 , 888 ± 2 cm -1 , 928 ± 2 cm -1 , 957 ± 2 cm - 1 , 984 ± 2 cm -1 , 1028 ± 2 cm -1 , 1035 ± 2 cm -1 , 1047 ± 2 cm -1 , 1073 ± 2 cm -1 , 1136 ± 2 cm -1 , 1174 ± 2 cm -1 , 1199 ± 2 cm -1 , 1216 ± 2 cm -1 1222 ± 2 cm -1 1265 ± 2 cm -1 , 1352 ± 2 cm -1 , 1628 ± 2 cm -1 and 2845 ± 2 cm -1 and other Raman A group of spectral bands.

本發明另一方面涉及一種如上述製備晶形B之方法，其包括以下步驟：(a-1)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-s螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺之鹽酸鹽由自由鹼溶液或懸浮液中沉 澱出。 Another aspect of the invention relates to a process for the preparation of Form B as described above, which comprises the steps of: (a-1) (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl- 4',9'-dihydro-3'Hs spiro [cyclohexane-1,1'-pyrano[3,4,b]indole]-4-amine hydrochloride salt from free base solution or suspension Liquid sinking Drain.

可採用熟知此技術領域者已知之傳統溶媒做為此類溶液或懸浮液之溶媒，特別是水或有機溶媒等選自由醇類，例如甲醇、乙醇、正丙醇、異丙醇與正丁醇；酯類，例如乙酸乙酯、乙酸正丙酯、乙酸異丙酯、乙酸正丁酯與乙酸異丁酯；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；醚類，例如甲基叔丁基醚、二***、四氫呋喃、二異丙醚與1,4-二氧陸圜；腈類，例如乙腈；芳香族烴，例如甲苯；飽和烴基，例如正戊烷、正己烷與正庚烷；氯化烴，例如二氯甲烷與三氯甲烷；及N-甲基-2-吡咯啶酮、二甲基甲醯胺與二甲亞碸；及其混合物組成之群組。 A conventional solvent known to those skilled in the art can be used as a solvent for such a solution or suspension, and particularly water or an organic solvent or the like is selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol. ; esters, such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; ketones, such as acetone, 2-butanone, pentan-2-one, pent-3- Ketone, hexan-2-one and hexan-3-one; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, diisopropyl ether and 1,4-dioxane; nitriles such as acetonitrile; Aromatic hydrocarbons such as toluene; saturated hydrocarbon groups such as n-pentane, n-hexane and n-heptane; chlorinated hydrocarbons such as dichloromethane and chloroform; and N-methyl-2-pyrrolidone, dimethyl a group consisting of methotrexate and dimethyl hydrazine; and mixtures thereof.

於一特佳實施例中，其有機溶媒為丙酮與四氫呋喃之混合物。較佳地，丙酮與四氫呋喃之比例係介於100：1至1：1之範圍之間，以75：1至2：1之範圍更佳，以50：1至5：1之範圍又更佳，40：1至10：1之範圍再更佳，以35：1至15：1之範圍最佳，以30：1至15：1(體積/體積比)之範圍為首選。 In a particularly preferred embodiment, the organic solvent is a mixture of acetone and tetrahydrofuran. Preferably, the ratio of acetone to tetrahydrofuran is between 100:1 and 1:1, more preferably in the range of 75:1 to 2:1, and even more preferably in the range of 50:1 to 5:1. The range of 40:1 to 10:1 is even better, with the range of 35:1 to 15:1 being the best, and the range of 30:1 to 15:1 (volume/volume ratio) being preferred.

可藉由添加氯化氫進行步驟(a-1)。 Step (a-1) can be carried out by adding hydrogen chloride.

於一較佳實施例中，所添加之氯化氫為氯化氫氣之形式。 In a preferred embodiment, the hydrogen chloride added is in the form of hydrogen chloride.

於另一較佳實施例中，氯化氫係藉由進行反應之方式原位生成，例如藉由於一水性溶液中添加三甲基氯矽烷。 In another preferred embodiment, hydrogen chloride is formed in situ by reaction, for example by the addition of trimethylchlorodecane to an aqueous solution.

於又另一較佳實施例中，氯化氫為液體形式。 In yet another preferred embodiment, the hydrogen chloride is in liquid form.

於一較佳實施例中，其溶液為一溶於有機溶媒之氯化氫溶液，以醇類，例如乙醇、異丙醇與正丁醇；及醚類，例如二***、二異丙醚、四氫呋喃、甲基四氫呋喃與1,4-二氧陸圜為首選。 In a preferred embodiment, the solution is a hydrogen chloride solution dissolved in an organic solvent, such as alcohol, such as ethanol, isopropanol and n-butanol; and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, Methyltetrahydrofuran and 1,4-dioxane are preferred.

於一特佳實施例中，其溶液為溶於一水性溶媒之氯化氫溶液，以氫氯酸特佳。 In a particularly preferred embodiment, the solution is a hydrogen chloride solution dissolved in an aqueous solvent, particularly preferably hydrochloric acid.

較佳地，含氯化氫溶液與自由鹼溶液含有相同溶媒。 Preferably, the hydrogen chloride containing solution contains the same solvent as the free base solution.

較佳地，該溶液所含之氯化氫濃度係介於0.01 mol/L至15 mol/L之範圍之間，以0.02 mol/L至12.5 mol/L之範圍更佳，以0.05 mol/L至10 mol/L之範圍又更佳，以0.1 mol/L to 7.5 mol/L之範圍再更佳，以0.2 mol/L至10 mol/L之範圍最佳，以0.3 mol/L至5 mol/L之範圍為首選。 Preferably, the solution contains a concentration of hydrogen chloride in the range of 0.01 mol/L to 15 mol/L, more preferably in the range of 0.02 mol/L to 12.5 mol/L, and 0.05 mol/L to 10 The range of mol/L is better, preferably in the range of 0.1 mol/L to 7.5 mol/L, and most preferably in the range of 0.2 mol/L to 10 mol/L, from 0.3 mol/L to 5 mol/L. The range is preferred.

較佳地，添加於該自由鹼溶液或懸浮液之氯化氫量為莫耳過剩量。 Preferably, the amount of hydrogen chloride added to the free base solution or suspension is a molar excess.

較佳地，於根據本發明之方法中，步驟(a-1)係於相應溶媒之沸點或較低之溫度中進行，以不高於80℃之溫度較佳，以不高於60℃更佳，以不高於40℃又更佳，以20至40℃之溫度範圍為首選。 Preferably, in the method according to the present invention, the step (a-1) is carried out at a boiling point or a lower temperature of the corresponding solvent, preferably at a temperature not higher than 80 ° C, and more preferably not higher than 60 ° C. Preferably, it is preferably not higher than 40 ° C, and the temperature range of 20 to 40 ° C is preferred.

較佳地，於根據本發明之方法中，於步驟(a-1)得到之懸浮液係經至少1小時之攪拌，以至少4小時較佳，以至少6小時更佳，以至少12小時又更佳，以至少18小時再更佳，以至少1天最佳，以至少2天為首選。 Preferably, in the method according to the present invention, the suspension obtained in the step (a-1) is stirred for at least 1 hour, preferably at least 4 hours, more preferably at least 6 hours, and at least 12 hours. More preferably, at least 18 hours is better, at least 1 day is best, and at least 2 days is preferred.

較佳地，根據本發明之方法另包括以下步驟：(b-1)分離，以將於步驟(a-1)得到之固體過濾出較佳。 Preferably, the method according to the invention further comprises the step of: (b-1) separating, preferably filtering the solid obtained in step (a-1).

較佳地，根據本發明之方法另包括以下步驟：(c-1)將由步驟(b-1)得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (c-1) drying the solid obtained from step (b-1).

於一較佳實施例中，步驟(c-1)係於空氣或惰性氣體氣流中進行，例如氬氣或氮氣氣流。 In a preferred embodiment, step (c-1) is carried out in a stream of air or an inert gas, such as an argon or nitrogen stream.

於另一較佳實施例中，步驟(c-1)係於真空狀態進行，以0至900 mbar之真空狀態更佳，以1至500 mbar之真空狀態又更佳，以10至200 mbar之真空狀態為首選。 In another preferred embodiment, step (c-1) is carried out in a vacuum state, preferably in a vacuum of 0 to 900 mbar, more preferably in a vacuum of 1 to 500 mbar, and in a range of 10 to 200 mbar. Vacuum is preferred.

較佳地，於根據本發明之方法中，步驟(c-1)係於0至60℃之溫度範圍中進行，以10至50℃較佳，以20至40℃更佳。 Preferably, in the method according to the present invention, the step (c-1) is carried out in a temperature range of from 0 to 60 ° C, preferably from 10 to 50 ° C, more preferably from 20 to 40 ° C.

於另一較佳實施例中，其方法包括以下步驟：(a-2)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己 烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽以一溶媒溶解。 In another preferred embodiment, the method comprises the steps of: (a-2) (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9' -dihydro-3'H-spiro[cyclohexyl] The alkal-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride is dissolved in a solvent.

可採用熟知此技術領域者已知之傳統溶媒做為此類懸浮液之溶媒，特別是選自由醇類，例如甲醇、乙醇、正丙醇、異丙醇與正丁醇；酯類，例如乙酸乙酯、乙酸正丙酯、乙酸異丙酯、乙酸正丁酯與乙酸異丁酯；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；醚類，例如甲基叔丁基醚、二***、四氫呋喃、二異丙醚與1,4-二氧陸圜；腈類，例如乙腈；芳香族烴，例如甲苯；氯化烴，例如二氯甲烷與三氯甲烷；及N-甲基-2-吡咯啶酮、二甲基甲醯胺與二甲亞碸；及其混合物等有機溶媒組成之群組。飽和烴基，例如正戊烷、正己烷與正庚烷，及水較不適用，(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽於這些物質中僅有極低之溶解度。 Conventional solvents known to those skilled in the art can be employed as a solvent for such suspensions, particularly selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol; esters such as acetic acid B. Ester, n-propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; ketones such as acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one With hexanone; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, diisopropyl ether and 1,4-dioxane; nitriles such as acetonitrile; aromatic hydrocarbons such as toluene; A group of chlorinated hydrocarbons, such as dichloromethane and chloroform; and N-methyl-2-pyrrolidone, dimethylformamide, and dimethylhydrazine; and mixtures thereof, such as organic solvents. Saturated hydrocarbon groups such as n-pentane, n-hexane and n-heptane, and water are less suitable, (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9' -Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride has only very low solubility in these materials.

較佳地，該溶媒係選自二氯甲烷與二氯甲烷與甲醇之混合物。 Preferably, the solvent is selected from the group consisting of dichloromethane and a mixture of dichloromethane and methanol.

於一較佳實施例中，其有機溶媒為二氯甲烷與甲醇之混合物。較佳地，二氯甲烷與甲醇之比例係介於10：1至1：10之範圍之間，以7：1至1：5之範圍更佳，以6：1至1：3之範圍又更佳，以5：1至1：1之範圍再更佳，以4：1至2：1之範圍最佳，以3.5：1至2.5：1之範圍為首選(體積/體積比)。 In a preferred embodiment, the organic solvent is a mixture of dichloromethane and methanol. Preferably, the ratio of dichloromethane to methanol is between 10:1 and 1:10, more preferably in the range of 7:1 to 1:5, and in the range of 6:1 to 1:3. More preferably, it is preferably in the range of 5:1 to 1:1, preferably in the range of 4:1 to 2:1, and preferably in the range of 3.5:1 to 2.5:1 (volume/volume ratio).

較佳地，於根據本發明之方法中，步驟(a-2)係於相應溶媒之沸點或較低之溫度中進行，以不高於80℃之溫度較佳，以不高於60℃更佳，以不高於40℃又更佳，以20至40℃之溫度範圍為首選。 Preferably, in the method according to the present invention, the step (a-2) is carried out at a boiling point or a lower temperature of the corresponding solvent, preferably at a temperature not higher than 80 ° C, and more preferably not higher than 60 ° C. Preferably, it is preferably not higher than 40 ° C, and the temperature range of 20 to 40 ° C is preferred.

於一特佳實施例中，根據本發明之方法另包括以下步驟：(b-2)將於步驟(a-2)得到之溶液中之溶媒蒸發。 In a particularly preferred embodiment, the process according to the invention further comprises the step of: (b-2) evaporating the solvent in the solution obtained in step (a-2).

適用於蒸發溶媒之方法已為熟知此技術領域者所知。較佳地，於根據本發明之方法中，溶媒係於空氣、空氣氣流或惰性氣體氣流中蒸發，特別是氬氣或氮氣氣流。然而，亦可將溶媒於真空狀態蒸發，例 如使用旋轉蒸發器。 Suitable methods for evaporating the solvent are known to those skilled in the art. Preferably, in the process according to the invention, the solvent is vaporized in a stream of air, air or inert gas, in particular an argon or nitrogen stream. However, the solvent can also be evaporated in a vacuum state, for example. Use a rotary evaporator.

較佳地，於根據本發明之方法中，溶媒係於室溫蒸發。 Preferably, in the process according to the invention, the solvent is evaporated at room temperature.

於另一較佳實施例中，其方法另包括以下步驟：(b-2')將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽由於步驟(a-2)得到之溶液中沉澱出。 In another preferred embodiment, the method further comprises the step of: (b-2')-(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4', 9'-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride obtained from step (a-2) Precipitated in the solution.

適用之沉澱方法已為熟知此技術領域者所知。於根據本發明之方法中，可藉由降低由步驟(a-2)得到之溶液之體積及/或將該溶液冷卻進行步驟(b-2')，以冷卻至最高15℃之溫度較佳，以最高10℃更佳，以最高4至8℃最佳，及/或藉由將該溶液冷卻，以冷卻至較根據步驟(a-2)之溫度低至少10℃之溫度較佳，以至少低30℃更佳，以至少低60℃又更佳。 Suitable precipitation methods are known to those skilled in the art. In the method according to the present invention, it is preferred to cool to a temperature of up to 15 ° C by lowering the volume of the solution obtained in the step (a-2) and/or cooling the solution to carry out the step (b-2'). More preferably at a maximum of 10 ° C, preferably at a maximum of 4 to 8 ° C, and/or by cooling the solution to a temperature of at least 10 ° C lower than the temperature according to step (a-2), preferably It is preferably at least 30 ° C lower, and more preferably at least 60 ° C lower.

於一較佳實施例中，步驟(b-2')係藉由添加介質進行，於該介質中，(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並-[3,4,b]吲哚]-4-胺鹽酸鹽於步驟(a-2)得到之溶液中僅有極低之溶解度(「反溶劑(anti-solvent)」)。該介質以選自由酯類，如乙酸乙酯、乙酸正丙酯、乙酸異丙酯、乙酸正丁酯與乙酸異丁酯；醚類，例如於甲基叔丁基醚、二***與二異丙醚；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；腈類，例如乙腈；啶、乙酸乙酯與水組成之群組較佳。特佳之介質為乙酸乙酯與乙腈。 In a preferred embodiment, step (b-2') is carried out by adding a medium in which (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl -4',9'-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano-[3,4,b]indole-4-amine hydrochloride in step (a -2) There is only a very low solubility ("anti-solvent") in the resulting solution. The medium is selected from the group consisting of esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; ethers such as methyl t-butyl ether, diethyl ether and diiso Propyl ether; ketones such as acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one and hexan-3-one; nitriles such as acetonitrile; pyridine, ethyl acetate and The group of water components is preferred. Particularly preferred media are ethyl acetate and acetonitrile.

對(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低溶解度之介質、沉澱劑或反溶劑之用量選擇，以可使溶解成分於添加後即開始沉澱較佳。 (1r,4r)-6'-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyridyl The argon [3,4,b]吲哚]-4-amine hydrochloride is selected only in the amount of a medium having a very low solubility, a precipitant or an anti-solvent, so that the dissolved component starts to precipitate immediately after the addition.

亦可將對(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低溶解度之介 質之總量分成數個份量，以分成2或3個份量較佳。於此實施例中，溶解成分以於添加最後一份量後開始沉澱較佳。 (1r,4r)-6'-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1 '-Pyrando[3,4,b]吲哚]-4-amine hydrochloride has only very low solubility The total amount of the mass is divided into several portions, and it is preferably divided into 2 or 3 portions. In this embodiment, it is preferred to dissolve the ingredients to initiate precipitation after the last amount is added.

溶解成分之沉澱反應，以添加沉澱劑後立即開始，以添加沉澱劑總量之後較佳，或者延遲2秒至120分鐘之後開始較佳。較佳地，溶解成分之沉澱反應以於最久90分鐘之期間內開始較佳，以最久60分鐘內更佳，以最久30分鐘內又更佳，以最久5分鐘內再更佳，以最久60秒內最佳，以最久10秒內特佳。 The precipitation reaction of the dissolved components is started immediately after the addition of the precipitating agent, preferably after the total amount of the precipitating agent is added, or after a delay of 2 seconds to 120 minutes. Preferably, the precipitation reaction of the dissolved component starts better during the longest period of 90 minutes, preferably in the longest 60 minutes, preferably in the longest 30 minutes, and preferably in the longest 5 minutes. It is best in the longest 60 seconds, and the best in 10 seconds.

較佳地，於根據本發明之方法中，步驟(b-2)或(b-2')後之所有步驟係係分別以介於40與0℃之間之溫度進行，以介於35與5℃之間更佳，以介於25與15℃之間又更佳。 Preferably, in the method according to the invention, all the steps after step (b-2) or (b-2') are carried out at a temperature between 40 and 0 ° C, respectively, to More preferably between 5 ° C and even better between 25 and 15 ° C.

較佳地，於根據本發明之方法中，於步驟(b-2')得到之懸浮液係經至少1分鐘之攪拌，以至少2分鐘較佳，以至少3分鐘更佳，以至少5分鐘最佳。 Preferably, in the method according to the present invention, the suspension obtained in the step (b-2') is stirred for at least 1 minute, preferably at least 2 minutes, more preferably at least 3 minutes, and at least 5 minutes. optimal.

較佳地，根據本發明之方法另包括以下步驟：(c-2')分離，以將於步驟(b-2')得到之沉澱物過濾出較佳。 Preferably, the method according to the invention further comprises the step of: (c-2') separating, preferably filtering the precipitate obtained in step (b-2').

較佳地，根據本發明之方法另包括以下步驟：(d-2')將由步驟(c-2')得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (d-2') drying the solid obtained from step (c-2').

較佳地，於根據本發明之方法中，步驟(d-2')係於空氣或惰性氣體氣流中進行，例如氬氣與氮氣氣流。 Preferably, in the process according to the invention, step (d-2') is carried out in a stream of air or an inert gas, such as a stream of argon and nitrogen.

於又另一較佳實施例中，其方法包括以下步驟：(a-3)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽懸浮於一溶媒中。 In still another preferred embodiment, the method comprises the steps of: (a-3) (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9 '-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride was suspended in a solvent.

可採用熟知此技術領域者已知之傳統溶媒做為此類懸浮液之溶媒，特別是水與有機溶媒等選自由醇類如甲醇、乙醇、正丙醇、異丙醇與正丁醇；酯類，例如乙酸乙酯、乙酸正丙酯、乙酸異丙酯、乙酸正丁酯與乙酸異丁酯；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3- 酮、己-2-酮與己-3-酮；醚類，例如甲基叔丁基醚、二***、四氫呋喃、二異丙醚與1,4-二氧陸圜；腈類，例如乙腈；芳香族烴，例如甲苯；飽和烴基，例如正戊烷、正己烷與正庚烷；氯化烴，例如二氯甲烷與三氯甲烷；及N-甲基-2-吡咯啶酮、二甲基甲醯胺與二甲亞碸；及其混合物組成之群組。 A conventional solvent known to those skilled in the art can be used as a solvent for such a suspension, and particularly water and an organic solvent are selected from alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol; For example, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; ketones such as acetone, 2-butanone, pentan-2-one, pent-3- Ketone, hexan-2-one and hexan-3-one; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, diisopropyl ether and 1,4-dioxane; nitriles such as acetonitrile; Aromatic hydrocarbons such as toluene; saturated hydrocarbon groups such as n-pentane, n-hexane and n-heptane; chlorinated hydrocarbons such as dichloromethane and chloroform; and N-methyl-2-pyrrolidone, dimethyl a group consisting of methotrexate and dimethyl hydrazine; and mixtures thereof.

於一較佳實施例中，步驟(a-3)係於不高於100℃之溫度中進行，以不高於90℃較佳，以不高於80℃更佳，以不高於60℃又更佳，以不高於40℃再更佳，以15至35℃之溫度範圍為首選。 In a preferred embodiment, the step (a-3) is carried out at a temperature not higher than 100 ° C, preferably not higher than 90 ° C, more preferably not higher than 80 ° C, and not higher than 60 ° C. More preferably, it is preferably no more than 40 ° C, and a temperature range of 15 to 35 ° C is preferred.

於另一較佳實施例中，步驟(a-3)係於100至40℃之溫度範圍中進行，以90至50℃更佳，以85至60℃最佳。 In another preferred embodiment, step (a-3) is carried out in a temperature range of from 100 to 40 ° C, more preferably from 90 to 50 ° C, and most preferably from 85 to 60 ° C.

較佳地，於根據本發明之方法中，於步驟(a-3)得到之懸浮液係經至少2小時之攪拌，以至少4小時較佳，以至少8小時再更佳，以至少12小時又更佳，以至少16小時再更佳，以至少24小時最佳，以至少2天為首選。 Preferably, in the method according to the present invention, the suspension obtained in the step (a-3) is stirred for at least 2 hours, preferably at least 4 hours, more preferably at least 8 hours, and at least 12 hours. It is even better, preferably at least 16 hours, best for at least 24 hours, and at least 2 days is preferred.

較佳地，根據本發明之方法另包括以下步驟：(b-3)分離，已將於步驟(a-3)得到之固體過濾出較佳。 Preferably, the method according to the invention further comprises the step of: (b-3) separating, the solid which has been obtained in step (a-3) is preferably filtered.

較佳地，根據本發明之方法另包括以下步驟：(c-3)將於步驟(b-3)得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (c-3) drying the solid obtained in step (b-3).

於根據本發明之方法中，步驟(c-3)可於空氣或惰性氣體氣流中進行，例如氬氣或氮氣氣流。然而，於真空狀態進行乾燥較佳，以0至900 mbar之真空狀態更佳，以1至500 mbar之真空狀態又更加，以10至200 mbar之真空狀態為首選。 In the process according to the invention, step (c-3) can be carried out in a stream of air or an inert gas, such as an argon or nitrogen stream. However, it is preferred to carry out the drying in a vacuum state, preferably in a vacuum of 0 to 900 mbar, and more preferably in a vacuum of 1 to 500 mbar, and a vacuum of 10 to 200 mbar is preferred.

較佳地，於根據本發明之方法中，步驟(c-3)係於介於0至60℃之溫度範圍中進行，以10至50℃較佳，以20至40℃更佳。 Preferably, in the method according to the present invention, the step (c-3) is carried out in a temperature range of from 0 to 60 ° C, preferably from 10 to 50 ° C, more preferably from 20 to 40 ° C.

本發明另一方面涉及利用上述方法獲得之晶形B。 Another aspect of the invention relates to Form B obtained by the above method.

本發明另一方面涉及晶形C。 Another aspect of the invention relates to Form C.

較佳地，根據本發明之晶形C具有一個或更多個選自由9.1±0.2(2Θ)、11.2±0.2(2Θ)、18.2±0.2(2Θ)、18.8±0.2(2Θ)、19.1±0.2(2Θ)、19.3±0.2(2Θ)、24.0±0.2(2Θ)、27.5±0.2(2Θ)與28.2±0.2(2Θ)等X光繞射波峰組成之群組。於數個實施例中，其晶形包含位於11.2±0.2(2Θ)、18.2±0.2(2Θ)與27.5±0.2(2Θ)之X光繞射波峰。於數個較佳實施例中，其晶形包含一位於18.2±0.2(2Θ)之X光繞射波峰。 Preferably, the crystalline form C according to the present invention has one or more selected from the group consisting of 9.1 ± 0.2 (2 Θ), 11.2 ± 0.2 (2 Θ), 18.2 ± 0.2 (2 Θ), 18.8 ± 0.2 (2 Θ), 19.1 ± 0.2 ( 2Θ), 19.3±0.2 (2Θ), 24.0±0.2 (2Θ), 27.5±0.2 (2Θ) and 28.2±0.2 (2Θ) and other groups of X-ray diffraction peaks. In several embodiments, the crystalline form comprises X-ray diffraction peaks at 11.2 ± 0.2 (2 Θ), 18.2 ± 0.2 (2 Θ), and 27.5 ± 0.2 (2 Θ). In several preferred embodiments, the crystal form comprises an X-ray diffraction peak at 18.2 ± 0.2 (2 Å).

於數個較佳實施例中，晶形C包含位於9.1±0.2(2Θ)、11.2±0.2(2Θ)、18.2±0.2(2Θ)、18.8±0.2(2Θ)、19.3±0.2(2Θ)、24.0±0.2(2Θ)、27.4±0.2(2Θ)、28.2±0.2(2Θ)及選擇性地19.1±0.2(2Θ)之X光繞射波峰。 In several preferred embodiments, Form C is comprised of 9.1 ± 0.2 (2 Θ), 11.2 ± 0.2 (2 Θ), 18.2 ± 0.2 (2 Θ), 18.8 ± 0.2 (2 Θ), 19.3 ± 0.2 (2 Θ), 24.0 ± X-ray diffraction peaks of 0.2 (2 Θ), 27.4 ± 0.2 (2 Θ), 28.2 ± 0.2 (2 Θ), and selectively 19.1 ± 0.2 (2 Θ).

根據本發明之晶形C可額外具有至少一個選自由22.4±0.2(2Θ)、23.8±0.2(2Θ)、24.3±0.2(2Θ)、26.1±0.2(2Θ)、26.4±0.2(2Θ)、27.9±0.2(2Θ)、31.6±0.2(2Θ)與34.1±0.2(2Θ)等X光繞射波峰組成之群組。 The crystal form C according to the present invention may additionally have at least one selected from the group consisting of 22.4 ± 0.2 (2 Θ), 23.8 ± 0.2 (2 Θ), 24.3 ± 0.2 (2 Θ), 26.1 ± 0.2 (2 Θ), 26.4 ± 0.2 (2 Θ), 27.9 ± A group consisting of 0.2 (2 Θ), 31.6 ± 0.2 (2 Θ) and 34.1 ± 0.2 (2 Θ) X-ray diffraction peaks.

此外，根據本發明之晶形C之特徵可為其具有一個或更多個選自由9.1±0.2(2Θ)、11.2±0.2(2Θ)、18.2±0.2(2Θ)、18.8±0.2(2Θ)、19.1±0.2(2Θ)、19.3±0.2(2Θ)、24.0±0.2(2Θ)、27.5±0.2(2Θ)與28.2±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由22.4±0.2(2Θ)、23.8±0.2(2Θ)、24.3±0.2(2Θ)、26.1±0.2(2Θ)、26.4±0.2(2Θ)、27.9±0.2(2Θ)、31.6±0.2(2Θ)與34.1±0.2(2Θ)等X光繞射波峰組成之群組，其選擇性地具有至少一個選自由17.0±0.2(2Θ)、24.5±0.2(2Θ)、26.7±0.2(2Θ)、29.2±0.2(2Θ)、29.8±0.2(2Θ)、32.0±0.2(2Θ)、34.3±0.2(2Θ)與34.8±0.2(2Θ)等X光繞射波峰組成之群組。 Further, the crystal form C according to the present invention may be characterized by having one or more selected from the group consisting of 9.1 ± 0.2 (2 Θ), 11.2 ± 0.2 (2 Θ), 18.2 ± 0.2 (2 Θ), 18.8 ± 0.2 (2 Θ), 19.1. Groups of X-ray diffraction peaks such as ±0.2 (2Θ), 19.3±0.2 (2Θ), 24.0±0.2 (2Θ), 27.5±0.2 (2Θ), and 28.2±0.2 (2Θ), and optionally one or More selected from 22.4 ± 0.2 (2 Θ), 23.8 ± 0.2 (2 Θ), 24.3 ± 0.2 (2 Θ), 26.1 ± 0.2 (2 Θ), 26.4 ± 0.2 (2 Θ), 27.9 ± 0.2 (2 Θ), 31.6 ± 0.2 (2Θ) and a group of X-ray diffraction peaks such as 34.1±0.2 (2Θ), which selectively have at least one selected from the group consisting of 17.0±0.2 (2Θ), 24.5±0.2 (2Θ), and 26.7±0.2 (2Θ). Groups of X-ray diffraction peaks such as 29.2±0.2 (2Θ), 29.8±0.2 (2Θ), 32.0±0.2 (2Θ), 34.3±0.2 (2Θ), and 34.8±0.2 (2Θ).

根據本發明之晶形C之特徵可為其進一步具有一個或更多個選自由9.1±0.2(2Θ)、11.2±0.2(2Θ)、18.2±0.2(2Θ)、18.8±0.2(2Θ)、19.1±0.2(2Θ)、19.3±0.2(2Θ)、24.0±0.2(2Θ)、27.5±0.2(2Θ)與28.2±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由22.4 ±0.2(2Θ)、23.8±0.2(2Θ)、24.3±0.2(2Θ)、26.1±0.2(2Θ)、26.4±0.2(2Θ)、27.9±0.2(2Θ)、31.6±0.2(2Θ)與34.1±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由17.0±0.2(2Θ)、24.5±0.2(2Θ)、26.7±0.2(2Θ)、29.2±0.2(2Θ)、29.8±0.2(2Θ)、32.0±0.2(2Θ)、34.3±0.2(2Θ)與34.8±0.2(2Θ)等X光繞射波峰組成之群組，其額外具有至少一個選自由7.8±0.2(2Θ)、17.3±0.2(2Θ)、21.7±0.2(2Θ)與23.4±0.2(2Θ)等X光繞射波峰組成之群組。 The crystal form C according to the present invention may be further characterized by having one or more selected from the group consisting of 9.1 ± 0.2 (2 Θ), 11.2 ± 0.2 (2 Θ), 18.2 ± 0.2 (2 Θ), 18.8 ± 0.2 (2 Θ), 19.1 ± Groups of X-ray diffraction peaks such as 0.2 (2 Θ), 19.3 ± 0.2 (2 Θ), 24.0 ± 0.2 (2 Θ), 27.5 ± 0.2 (2 Θ), and 28.2 ± 0.2 (2 Θ), and optionally one or more Multiple selected from 22.4 ±0.2(2Θ), 23.8±0.2(2Θ), 24.3±0.2(2Θ), 26.1±0.2(2Θ), 26.4±0.2(2Θ), 27.9±0.2(2Θ), 31.6±0.2(2Θ) and 34.1± a group consisting of 0.2 (2 Θ) and other X-ray diffraction peaks, and optionally one or more selected from the group consisting of 17.0 ± 0.2 (2 Θ), 24.5 ± 0.2 (2 Θ), 26.7 ± 0.2 (2 Θ), 29.2 ± 0.2 (2Θ), 29.8±0.2 (2Θ), 32.0±0.2 (2Θ), 34.3±0.2 (2Θ), and 34.8±0.2 (2Θ) and other groups of X-ray diffraction peaks, which additionally have at least one selected from 7.8 Groups of X-ray diffraction peaks such as ±0.2 (2Θ), 17.3±0.2 (2Θ), 21.7±0.2 (2Θ), and 23.4±0.2 (2Θ).

所有2Θ值係指利用波長為1.54060 Å之CuKα輻射所測得之X射線繞射圖。 All 2 Θ values refer to X-ray diffraction patterns measured using CuKα radiation at a wavelength of 1.54060 Å.

根據本發明之晶形C之特徵可為其進一步具有至少一個選自由177±2 cm-1、1567±2 cm-1與1584±2 cm-1等拉曼光譜帶組成之群組。 The crystal form C according to the present invention may be characterized in that it further has at least one group selected from the group consisting of Raman spectral bands of 177 ± 2 cm -1 , 1567 ± 2 cm -1 and 1584 ± 2 cm -1 .

根據本發明之晶形C可進一步為其具有一個或更多個選自由177±2 cm-1、1567±2 cm-1與1584±2 cm-1等拉曼光譜帶組成之群組；及/或一個或更多個選自由158±2 cm-1、685±2 cm-1、918±2 cm-1、925±2 cm-1、1000±2 cm-1、1301±2 cm-1與3072±2 cm-1等拉曼光譜帶組成之群組；及/或一個或更多個選自由208±2 cm-1、253±2 cm-1、266±2 cm-1、370±2 cm-1、490±2 cm-1、600±2 cm-1、620±2 cm-1、628±2 cm-1、829±2 cm-1、1028±2 cm-1、1114±2 cm-1、1219±2 cm-1、1374±2 cm-1、1432±2 cm-1、1454±2 cm-1、1464±2 cm-1、1481±2 cm-1、1600±2 cm-1與2959±2 cm-1等拉曼光譜帶組成之群組。 The crystal form C according to the present invention may further have one or more groups selected from the group consisting of Raman spectral bands of 177 ± 2 cm -1 , 1567 ± 2 cm -1 and 1584 ± 2 cm -1 ; and / Or one or more selected from the group consisting of 158±2 cm -1 , 685 ± 2 cm -1 , 918 ± 2 cm -1 , 925 ± 2 cm -1 , 1000 ± 2 cm -1 , 1301 ± 2 cm -1 and a group consisting of 3072 ± 2 cm -1 and other Raman spectral bands; and / or one or more selected from the group consisting of 208 ± 2 cm -1 , 253 ± 2 cm -1 , 266 ± 2 cm -1 , 370 ± 2 Cm -1 , 490 ± 2 cm -1 , 600 ± 2 cm -1 , 620 ± 2 cm -1 , 628 ± 2 cm -1 , 829 ± 2 cm -1 , 1028 ± 2 cm -1 , 1114 ± 2 cm -1 , 1219 ± 2 cm -1 , 1374 ± 2 cm -1 , 1432 ± 2 cm -1 , 1454 ± 2 cm -1 , 1464 ± 2 cm -1 , 1481 ± 2 cm -1 , 1600 ± 2 cm - 1 is a group consisting of Raman spectral bands such as 2959±2 cm -1 .

根據本發明之晶形C之特徵可為其進一步具有一個或更多個選自由322±2 cm-1、395±2 cm-1、429±2 cm-1、471±2 cm-1、516±2 cm-1、538±2 cm-1、567±2 cm-1、710±2 cm-1、772±2 cm-1、786±2 cm-1、889±2 cm-1、954±2 cm-1、986±2 cm-1、1055±2 cm-1、1076±2 cm-1、1136±2 cm-1、1167±2 cm-1、1200±2 cm-1、1267±2 cm-1、1359±2 cm-1、1628±2 cm-1、2842±2 cm-1、2880±2 cm-1、2901±2 cm-1、2927±2 cm-1、2994±2 cm-1、3031±2 cm-1與3045±2 cm-1等拉曼光譜帶組成之群組。 The crystal form C according to the present invention may be further characterized by having one or more selected from the group consisting of 322 ± 2 cm -1 , 395 ± 2 cm -1 , 429 ± 2 cm -1 , 471 ± 2 cm -1 , 516 ± 2 cm -1 , 538 ± 2 cm -1 , 567 ± 2 cm -1 , 710 ± 2 cm -1 , 772 ± 2 cm -1 , 786 ± 2 cm -1 , 889 ± 2 cm -1 , 954 ± 2 Cm -1 , 986 ± 2 cm -1 , 1055 ± 2 cm -1 , 1076 ± 2 cm -1 , 1136 ± 2 cm -1 , 1167 ± 2 cm -1 , 1200 ± 2 cm -1 , 1267 ± 2 cm -1 , 1359 ± 2 cm -1 , 1628 ± 2 cm -1 , 2842 ± 2 cm -1 , 2880 ± 2 cm -1 , 2901 ± 2 cm -1 , 2927 ± 2 cm -1 , 2994 ± 2 cm - 1 , a group consisting of 3031 ± 2 cm -1 and 3045 ± 2 cm -1 and other Raman spectral bands.

本發明另一方面涉及一種製備上述晶形C之方法，其包括以下步驟：(a-1)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺之鹽酸鹽由自由鹼溶液或懸浮液中沉澱出。 Another aspect of the invention relates to a process for the preparation of the above Form C, which comprises the steps of: (a-1) (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4 ',9'-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride salt from free base solution or suspension Precipitated in the liquid.

該溶液或懸浮液以含有水分較佳。於此實施例中，該溶液或懸浮液已另含水溶性有機溶媒較佳，例如丙酮或四氫呋喃。 The solution or suspension preferably contains moisture. In this embodiment, the solution or suspension already contains a water soluble organic solvent, such as acetone or tetrahydrofuran.

可做為該溶液或懸浮液之溶媒之特佳溶媒為四氫呋喃與水之混合物。 A particularly preferred solvent for use as a solvent for the solution or suspension is a mixture of tetrahydrofuran and water.

於一特佳實施例中，其有機溶媒為水與四氫呋喃之混合物。較佳地，水與四氫呋喃之比例係介於50：1至1：50之範圍之間，以30：1至1：20之範圍更佳，以20：1至1：10之範圍又更佳，以15：1至1：5之範圍再更佳，以10：1至1：2之範圍最佳，以8：1至1：1之範圍為首選(體積/體積比)。 In a particularly preferred embodiment, the organic solvent is a mixture of water and tetrahydrofuran. Preferably, the ratio of water to tetrahydrofuran is between 50:1 and 1:50, more preferably in the range of 30:1 to 1:20, and more preferably in the range of 20:1 to 1:10. It is better in the range of 15:1 to 1:5, and the range of 10:1 to 1:2 is the best, and the range of 8:1 to 1:1 is preferred (volume/volume ratio).

可藉由添加氯化氫進行步驟(a-1)。 Step (a-1) can be carried out by adding hydrogen chloride.

於一較佳實施例中，所添加之氯化氫為氯化氫氣之形式。 In a preferred embodiment, the hydrogen chloride added is in the form of hydrogen chloride.

於另一較佳實施例中，氯化氫係藉由進行反應之方式原位生成，例如藉由於一水性溶液中添加三甲基氯矽烷。 In another preferred embodiment, hydrogen chloride is formed in situ by reaction, for example by the addition of trimethylchlorodecane to an aqueous solution.

於又另一較佳實施例中，氯化氫為液體形式。 In yet another preferred embodiment, the hydrogen chloride is in liquid form.

較佳地，該溶液為溶於一水性溶媒之氯化氫溶液，以氫氯酸特佳。 Preferably, the solution is a hydrogen chloride solution dissolved in an aqueous solvent, particularly preferably hydrochloric acid.

較佳地，該溶液所含之氯化氫之濃度係介於0.01 mol/L至15 mol/L之範圍之間，以介於0.02 mol/L至12.5 mol/L之範圍之間更佳，以介於0.05 mol/L至10 mol/L之範圍之間又更佳，以介於0.1 mol/L至7.5 mol/L之範圍之間又更佳，以介於0.2 mol/L至10 mol/L之範圍之間最佳，以介於0.3 mol/L至5 mol/L之範圍之間為首選。 Preferably, the concentration of hydrogen chloride contained in the solution is between 0.01 mol/L and 15 mol/L, and more preferably between 0.02 mol/L and 12.5 mol/L. More preferably in the range of 0.05 mol/L to 10 mol/L, more preferably in the range of 0.1 mol/L to 7.5 mol/L, and preferably in the range of 0.2 mol/L to 10 mol/L. The range is optimal between 0.3 mol/L and 5 mol/L.

較佳地，添加於該自由鹼溶液或懸浮液之氯化氫量為莫耳過剩量。 Preferably, the amount of hydrogen chloride added to the free base solution or suspension is a molar excess.

較佳地，於根據本發明之方法中，步驟(a-1)係於相應溶媒之沸點或較低之溫度中進行，以不高於80℃之溫度較佳，以不高於60℃更佳，以不高於40℃又更佳，以20至40℃之溫度範圍為首選。 Preferably, in the method according to the present invention, the step (a-1) is carried out at a boiling point or a lower temperature of the corresponding solvent, preferably at a temperature not higher than 80 ° C, and more preferably not higher than 60 ° C. Preferably, it is preferably not higher than 40 ° C, and the temperature range of 20 to 40 ° C is preferred.

較佳地，於根據本發明之方法中，於步驟(a-1)得到之懸浮液係經至少1小時之攪拌，以至少4小時較佳，以至少6小時更佳，以至少12小時又更佳，以至少18小時再更佳，以至少1天最佳。 Preferably, in the method according to the present invention, the suspension obtained in the step (a-1) is stirred for at least 1 hour, preferably at least 4 hours, more preferably at least 6 hours, and at least 12 hours. More preferably, at least 18 hours is better, and at least 1 day is best.

較佳地，根據本發明之方法另包括以下步驟：(b-1)分離，以將於步驟(a-1)得到之固體過濾出較佳。 Preferably, the method according to the invention further comprises the step of: (b-1) separating, preferably filtering the solid obtained in step (a-1).

較佳地，根據本發明之方法另包括以下步驟：(c-1)將由步驟(b-1)得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (c-1) drying the solid obtained from step (b-1).

於一較佳實施例中，步驟(c-1)係於至少50%之相對濕度中進行，以至少60%更佳，以至少70%又更佳，以至少75%再更佳，以至少79%最佳，以至少85%或至少95%為首選。 In a preferred embodiment, step (c-1) is carried out in at least 50% relative humidity, preferably at least 60%, at least 70%, more preferably at least 75%, and even more preferably at least 79% is best, with at least 85% or at least 95% preferred.

於另一較佳實施例中，步驟(c-1)係於真空狀態進行，以0至900 mbar之真空狀態較佳，以1至500之真空狀態更佳，以10至200 mbar之真空狀態特佳。於此實施例中，於步驟(b-1)得到之固體係經暴露於真空狀態最久12小時，以最久8小時更佳，以最久6小時更佳，以最久4小時又更佳，以最久2小時最佳，以最久小時1為首選。 In another preferred embodiment, step (c-1) is carried out under vacuum, preferably in a vacuum of 0 to 900 mbar, more preferably in a vacuum of 1 to 500, and in a vacuum of 10 to 200 mbar. Very good. In this embodiment, the solid obtained in the step (b-1) is exposed to a vacuum for a maximum of 12 hours, preferably as long as 8 hours, preferably as long as 6 hours, and as long as 4 hours and more. Good, with the longest 2 hours best, the longest hour 1 is preferred.

本發明另一方面涉及利用上述方法獲得之晶形C。 Another aspect of the invention relates to a crystalline form C obtained by the above method.

本發明另一方面涉及晶形D。 Another aspect of the invention relates to Form D.

較佳地，根據本發明之晶形D具有一個或更多個選自由16.3±0.2(2Θ)、18.3±0.2(2Θ)、18.9±0.2(2Θ)、19.6±0.2(2Θ)、23.7±0.2(2Θ)、24.3±0.2(2Θ)、27.6±0.2(2Θ)與28.9±0.2(2Θ)等X光繞射波峰組成之群組。於數個較佳實施例中，其晶形包含位於18.3±0.2(2Θ)、18.9±0.2(2Θ)與19.6±0.2(2Θ)之X光繞射波峰。於數個較佳實施例中，其晶形 包含一位於18.9±0.2(2Θ)之X光繞射波峰。 Preferably, the crystal form D according to the present invention has one or more selected from the group consisting of 16.3 ± 0.2 (2 Θ), 18.3 ± 0.2 (2 Θ), 18.9 ± 0.2 (2 Θ), 19.6 ± 0.2 (2 Θ), 23.7 ± 0.2 ( Groups of X-ray diffraction peaks such as 2Θ), 24.3±0.2 (2Θ), 27.6±0.2 (2Θ), and 28.9±0.2 (2Θ). In several preferred embodiments, the crystalline form comprises X-ray diffraction peaks at 18.3 ± 0.2 (2 Θ), 18.9 ± 0.2 (2 Θ), and 19.6 ± 0.2 (2 Θ). In several preferred embodiments, the crystal form Contains an X-ray diffraction peak at 18.9 ± 0.2 (2 Θ).

於數個較佳實施例中，晶形D包含位於18.3±0.2(2Θ)、18.9±0.2(2Θ)、19.6±0.2(2Θ)、23.7±0.2(2Θ)、24.3±0.2(2Θ)、28.9±0.2(2Θ)，選擇性地16.3±0.2(2Θ)，及選擇性地27.6±0.2(2Θ)之X光繞射波峰。 In several preferred embodiments, Form D is comprised of 18.3 ± 0.2 (2 Θ), 18.9 ± 0.2 (2 Θ), 19.6 ± 0.2 (2 Θ), 23.7 ± 0.2 (2 Θ), 24.3 ± 0.2 (2 Θ), 28.9 ± 0.2 (2 Θ), selectively 16.3 ± 0.2 (2 Θ), and optionally 27.6 ± 0.2 (2 Θ) X-ray diffraction peaks.

根據本發明之晶形D可選擇性地含有至少一個選自由12.9±0.2(2Θ)、16.9±0.2(2Θ)、20.2±0.2(2Θ)、21.6±0.2(2Θ)、22.0±0.2(2Θ)、23.3±0.2(2Θ)、24.7±0.2(2Θ)、28.6±0.2(2Θ)、31.3±0.2(2Θ)與31.6±0.2(2Θ)等X光繞射波峰組成之群組。 The crystal form D according to the present invention may optionally contain at least one selected from the group consisting of 12.9 ± 0.2 (2 Θ), 16.9 ± 0.2 (2 Θ), 20.2 ± 0.2 (2 Θ), 21.6 ± 0.2 (2 Θ), 22.0 ± 0.2 (2 Θ), A group consisting of X-ray diffraction peaks such as 23.3 ± 0.2 (2 Θ), 24.7 ± 0.2 (2 Θ), 28.6 ± 0.2 (2 Θ), 31.3 ± 0.2 (2 Θ), and 31.6 ± 0.2 (2 Θ).

此外，根據本發明之晶形D之特徵可為其具有一個或更多個選自由16.3±0.2(2Θ)、18.3±0.2(2Θ)、18.9±0.2(2Θ)、19.6±0.2(2Θ)、23.7±0.2(2Θ)、24.3±0.2(2Θ)、27.6±0.2(2Θ)與28.9±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由12.9±0.2(2Θ)、16.9±0.2(2Θ)、20.2±0.2(2Θ)、21.6±0.2(2Θ)、22.0±0.2(2Θ)、23.3±0.2(2Θ)、24.7±0.2(2Θ)、28.6±0.2(2Θ)、31.3±0.2(2Θ)與31.6±0.2(2Θ)等X光繞射波峰組組成之群組，其額外具有至少一個選自由12.6±0.2(2Θ)、15.6±0.2(2Θ)、25.8±0.2(2Θ)、26.4±0.2(2Θ)、29.6±0.2(2Θ)、30.0±0.2(2Θ)與33.1±0.2(2Θ)等X光繞射波峰組組成之群組。 Further, the crystal form D according to the present invention may be characterized by having one or more selected from the group consisting of 16.3 ± 0.2 (2 Θ), 18.3 ± 0.2 (2 Θ), 18.9 ± 0.2 (2 Θ), 19.6 ± 0.2 (2 Θ), 23.7. Groups of X-ray diffraction peaks such as ±0.2 (2Θ), 24.3±0.2 (2Θ), 27.6±0.2 (2Θ), and 28.9±0.2 (2Θ), and optionally one or more selected from 12.9± 0.2(2Θ), 16.9±0.2(2Θ), 20.2±0.2(2Θ), 21.6±0.2(2Θ), 22.0±0.2(2Θ), 23.3±0.2(2Θ), 24.7±0.2(2Θ), 28.6±0.2 a group consisting of (2Θ), 31.3±0.2 (2Θ) and 31.6±0.2 (2Θ) and other X-ray diffraction peak groups, which additionally have at least one selected from the group consisting of 12.6±0.2 (2Θ), 15.6±0.2 (2Θ), A group consisting of 25.8±0.2 (2Θ), 26.4±0.2 (2Θ), 29.6±0.2 (2Θ), 30.0±0.2 (2Θ) and 33.1±0.2 (2Θ) and other X-ray diffraction peak groups.

根據本發明之晶形D之特徵可為其另具一個或更多個選自由16.3±0.2(2Θ)、18.3±0.2(2Θ)、18.9±0.2(2Θ)、19.6±0.2(2Θ)、23.7±0.2(2Θ)、24.3±0.2(2Θ)、27.6±0.2(2Θ)與28.9±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由12.9±0.2(2Θ)、16.9±0.2(2Θ)、20.2±0.2(2Θ)、21.6±0.2(2Θ)、22.0±0.2(2Θ)、23.3±0.2(2Θ)、24.7±0.2(2Θ)、28.6±0.2(2Θ)、31.3±0.2(2Θ)與31.6±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由12.6±0.2(2Θ)、15.6±0.2(2Θ)、25.8±0.2(2Θ)、26.4±0.2(2Θ)、29.6±0.2(2Θ)、30.0±0.2(2Θ)與33.1±0.2(2Θ)等X光繞射波峰組成之群組，其額外具 有至少一個選自由7.8±0.2(2Θ)、9.1±0.2(2Θ)、9.5±0.2(2Θ)、10.8±0.2(2Θ)、11.0±0.2(2Θ)與14.1±0.2(2Θ)等X光繞射波峰組成之群組。 The crystal form D according to the present invention may be characterized in that it has one or more selected from the group consisting of 16.3 ± 0.2 (2 Θ), 18.3 ± 0.2 (2 Θ), 18.9 ± 0.2 (2 Θ), 19.6 ± 0.2 (2 Θ), 23.7 ± Groups of X-ray diffraction peaks such as 0.2 (2 Θ), 24.3 ± 0.2 (2 Θ), 27.6 ± 0.2 (2 Θ), and 28.9 ± 0.2 (2 Θ), and optionally one or more selected from 12.9 ± 0.2 (2Θ), 16.9±0.2(2Θ), 20.2±0.2(2Θ), 21.6±0.2(2Θ), 22.0±0.2(2Θ), 23.3±0.2(2Θ), 24.7±0.2(2Θ), 28.6±0.2( 2Θ), 31.3±0.2 (2Θ) and 31.6±0.2 (2Θ) and other groups of X-ray diffraction peaks, and optionally one or more selected from 12.6±0.2(2Θ), 15.6±0.2(2Θ ), a group consisting of 25.8 ± 0.2 (2 Θ), 26.4 ± 0.2 (2 Θ), 29.6 ± 0.2 (2 Θ), 30.0 ± 0.2 (2 Θ) and 33.1 ± 0.2 (2 Θ) X-ray diffraction peaks, There are at least one selected from the group consisting of 7.8 ± 0.2 (2 Θ), 9.1 ± 0.2 (2 Θ), 9.5 ± 0.2 (2 Θ), 10.8 ± 0.2 (2 Θ), 11.0 ± 0.2 (2 Θ) and 14.1 ± 0.2 (2 Θ) and other X-ray winding A group of wave peaks.

所有2Θ值係指利用波長為1.54060 Å之CuKα輻射所測得之X射線繞射圖。 All 2 Θ values refer to X-ray diffraction patterns measured using CuKα radiation at a wavelength of 1.54060 Å.

根據本發明之晶形D之特徵可為其進一步具有一個或更多個選自由161±2 cm-1、172±2 cm-1、180±2 cm-1、686±2 cm-1、919±2 cm-1、1004±2 cm-1、1299±2 cm-1、1567±2 cm-1、1573±2 cm-1、2912±2 cm-1、2957±2 cm-1、2981±2 cm-1與3071±2 cm-1等拉曼光譜帶組成之群組。 The crystal form D according to the present invention may be further characterized by having one or more selected from the group consisting of 161 ± 2 cm -1 , 172 ± 2 cm -1 , 180 ± 2 cm -1 , 686 ± 2 cm -1 , 919 ± 2 cm -1 , 1004 ± 2 cm -1 , 1299 ± 2 cm -1 , 1567 ± 2 cm -1 , 1573 ± 2 cm -1 , 2912 ± 2 cm -1 , 2957 ± 2 cm -1 , 2981 ± 2 A group consisting of a Raman spectral band such as cm -1 and 3071 ± 2 cm -1 .

根據本發明之晶形D之特徵可為其進一步具有一個或更多個選自由161±2 cm-1、172±2 cm-1、180±2 cm-1、686±2 cm-1、919±2 cm-1、1004±2 cm-1、1299±2 cm-1、1567±2 cm-1、1573±2 cm-1、2912±2 cm-1、2957±2 cm-1、2981±2 cm-1與3071±2 cm-1等拉曼光譜帶組成之群組；及/或一個或更多個選自由206±2 cm-1、252±2 cm-1、600±2 cm-1、829±2 cm-1、1308±2 cm-1、1374±2 cm-1、1443±2 cm-1、1466±2 cm-1與2875±2 cm-1等拉曼光譜帶組成之群組；及/或一個或更多個選自由278±2 cm-1、370±2 cm-1、392±2 cm-1、429±2 cm-1、490±2 cm-1、517±2 cm-1、620±2 cm-1、629±2 cm-1、676±2 cm-1、887±2 cm-1、983±2 cm-1、1028±2 cm-1、1035±2 cm-1、1045±2 cm-1、1116±2 cm-1、1161±2 cm-1、1197±2 cm-1、1217±2 cm-1、1263±2 cm-1、1355±2 cm-1、1627±2 cm-1、2845±2 cm-1與3038±2 cm-1等拉曼光譜帶組成之群組。 The crystal form D according to the present invention may be further characterized by having one or more selected from the group consisting of 161 ± 2 cm -1 , 172 ± 2 cm -1 , 180 ± 2 cm -1 , 686 ± 2 cm -1 , 919 ± 2 cm -1 , 1004 ± 2 cm -1 , 1299 ± 2 cm -1 , 1567 ± 2 cm -1 , 1573 ± 2 cm -1 , 2912 ± 2 cm -1 , 2957 ± 2 cm -1 , 2981 ± 2 a group consisting of a Raman spectral band such as cm -1 and 3071 ± 2 cm -1 ; and / or one or more selected from the group consisting of 206 ± 2 cm -1 , 252 ± 2 cm -1 , 600 ± 2 cm -1 a group consisting of 829±2 cm -1 , 1308±2 cm -1 , 1374±2 cm -1 , 1443±2 cm -1 , 1466±2 cm -1 and 2875±2 cm -1 , etc. And/or one or more selected from the group consisting of 278 ± 2 cm -1 , 370 ± 2 cm -1 , 392 ± 2 cm -1 , 429 ± 2 cm -1 , 490 ± 2 cm -1 , 517 ± 2 Cm -1 , 620 ± 2 cm -1 , 629 ± 2 cm -1 , 676 ± 2 cm -1 , 887 ± 2 cm -1 , 983 ± 2 cm -1 , 1028 ± 2 cm -1 , 1035 ± 2 cm -1 , 1045 ± 2 cm -1 , 1116 ± 2 cm -1 , 1161 ± 2 cm -1 , 1197 ± 2 cm -1 , 1217 ± 2 cm -1 , 1263 ± 2 cm -1 , 1355 ± 2 cm - 1 , 1627 ± 2 cm -1 , 2845 ± 2 cm -1 and 3038 ± 2 cm -1 and other groups of Raman spectral bands.

根據本發明晶形D之特徵可為其進一步具有一個或更多個選自由317±2 cm-1、401±2 cm-1、468±2 cm-1、538±2 cm-1、557±2 cm-1、569±2 cm-1、712±2 cm-1、771±2 cm-1、787±2 cm-1、869±2 cm-1、953±2 cm-1、1074±2 cm-1、1134±2 cm-1、1183±2 cm-1、1250±2 cm-1與1339±2 cm-1等拉曼光譜帶組成之群組。 The crystal form D according to the present invention may further have one or more selected from the group consisting of 317 ± 2 cm -1 , 401 ± 2 cm -1 , 468 ± 2 cm -1 , 538 ± 2 cm -1 , 557 ± 2 Cm -1 , 569 ± 2 cm -1 , 712 ± 2 cm -1 , 771 ± 2 cm -1 , 787 ± 2 cm -1 , 869 ± 2 cm -1 , 953 ± 2 cm -1 , 1074 ± 2 cm A group consisting of -1 , 1134 ± 2 cm -1 , 1183 ± 2 cm -1 , 1250 ± 2 cm -1 and 1339 ± 2 cm -1 and other Raman spectral bands.

本發明另一方面涉及一種上述製備晶形D之方法，其包括以下步 驟：(a-1)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽由自由鹼溶液或懸浮液中沉澱出。 Another aspect of the invention relates to a method of preparing the crystal form D described above, which comprises the following steps Step: (a-1) (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane -1,1'-pyrano[3,4,b]indole-4-amine hydrochloride is precipitated from a free base solution or suspension.

較佳地，該溶媒係選自由醇類，例如甲醇、乙醇、正丙醇、異丙醇與正丁醇；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；醚類，例如甲基叔丁基醚、二***、四氫呋喃、二異丙醚與1,4-二氧陸圜；氯化烴，例如二氯甲烷與三氯甲烷；及其混合物組成之群組。 Preferably, the solvent is selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol; ketones such as acetone, 2-butanone, pentan-2-one, pent-3- Ketone, hexan-2-one and hexan-3-one; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, diisopropyl ether and 1,4-dioxane; chlorinated hydrocarbons, for example two a group consisting of methyl chloride and chloroform; and mixtures thereof.

較佳地，該溶媒不含水分。 Preferably, the solvent is free of moisture.

特佳之溶媒係選自由甲苯、乙醇、正丙醇、異丙醇、正丁醇與2-丁酮組成之群組。 A particularly preferred solvent is selected from the group consisting of toluene, ethanol, n-propanol, isopropanol, n-butanol and 2-butanone.

可藉由添加氯化氫進行步驟(a-1)。 Step (a-1) can be carried out by adding hydrogen chloride.

於一較佳實施例中，所添加之氯化氫為氯化氫氣之形式。 In a preferred embodiment, the hydrogen chloride added is in the form of hydrogen chloride.

於另一較佳實施例中，氯化氫係藉由進行反應之方式原位生成，例如藉由於一水性溶液中添加三甲基氯矽烷。 In another preferred embodiment, hydrogen chloride is formed in situ by reaction, for example by the addition of trimethylchlorodecane to an aqueous solution.

於又另一較佳實施例中，氯化氫為液體形式。 In yet another preferred embodiment, the hydrogen chloride is in liquid form.

較佳地，該溶液係一溶於有機溶媒之氯化氫溶液，以醇類，例如乙醇、異丙醇與正丁醇為首選。 Preferably, the solution is a hydrogen chloride solution dissolved in an organic solvent, and alcohols such as ethanol, isopropanol and n-butanol are preferred.

較佳地，該溶液所含之氯化氫之濃度係介於0.01 mol/L至15 mol/L之範圍之間，以介於0.02 mol/L至12.5 mol/L之範圍更佳，以介於0.05 mol/L至10 mol/L之範圍又更佳，以介於0.1 mol/L至7.5 mol/L之範圍再更佳，以介於0.2 mol/L至10 mol/L之範圍最佳，以介於0.3 mol/L至5 mol/L之範圍為首選。 Preferably, the concentration of hydrogen chloride contained in the solution is in the range of 0.01 mol/L to 15 mol/L, more preferably in the range of 0.02 mol/L to 12.5 mol/L, and is 0.05. The range of mol/L to 10 mol/L is more preferably in the range of 0.1 mol/L to 7.5 mol/L, and preferably in the range of 0.2 mol/L to 10 mol/L. A range of from 0.3 mol/L to 5 mol/L is preferred.

較佳地，添加於該自由鹼溶液或懸浮液之氯化氫量為莫耳過剩量。 Preferably, the amount of hydrogen chloride added to the free base solution or suspension is a molar excess.

較佳地，於根據本發明之方法中，步驟(a-1)係於相應溶媒之沸點 或較低之溫度中進行，以不高於80℃之溫度較佳，以不高於60℃更佳，以不高於40℃又更佳，以20至40℃之溫度範圍為首選。 Preferably, in the method according to the invention, step (a-1) is based on the boiling point of the corresponding solvent It is preferably carried out at a lower temperature, preferably at a temperature not higher than 80 ° C, more preferably not higher than 60 ° C, more preferably not higher than 40 ° C, and preferably having a temperature range of 20 to 40 ° C.

較佳地，於根據本發明之方法中，於步驟(a-1)得到之懸浮液係經至少1分鐘之攪拌，以至少2分鐘較佳，以至少3分鐘更佳，以至少5分鐘又更佳，以至少10分鐘再更佳，以至少20分鐘最佳，以至少30分鐘為首選。 Preferably, in the method according to the present invention, the suspension obtained in the step (a-1) is stirred for at least 1 minute, preferably at least 2 minutes, more preferably at least 3 minutes, and at least 5 minutes. More preferably, it is preferably at least 10 minutes, preferably at least 20 minutes, and at least 30 minutes is preferred.

於另一較佳實施例中，於步驟(a-1)得到之懸浮液係經最久1天之攪拌，以最久12小時較佳，以最久6小時更佳，以最久2小時又更佳，以最久60分鐘再更佳，以最久45分鐘最佳，以最久30分鐘為首選。 In another preferred embodiment, the suspension obtained in the step (a-1) is stirred for a maximum of one day, preferably for a maximum of 12 hours, preferably for a maximum of 6 hours, and for a maximum of 2 hours. It is even better, with a maximum of 60 minutes and a better, with a maximum of 45 minutes, with a maximum of 30 minutes as the first choice.

較佳地，根據本發明之方法另包括以下步驟：(b-1)分離，以將於步驟(a-1).得到之固體過濾出較佳。 Preferably, the method according to the invention further comprises the step of: (b-1) separating, preferably filtering the solid obtained in step (a-1).

較佳地，根據本發明之方法另包括以下步驟：(c-1)將由步驟(b-1)得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (c-1) drying the solid obtained from step (b-1).

於一較佳實施例中，步驟(c-1)係於空氣或惰性氣體氣流中進行，例如氬氣或氮氣氣流。 In a preferred embodiment, step (c-1) is carried out in a stream of air or an inert gas, such as an argon or nitrogen stream.

於另一較佳實施例中，步驟(c-1)係於真空狀態進行，以0至900 mbar之真空狀態較更佳，以1至500 mbar之真空狀態又更佳，以10至200之真空狀態為首選。 In another preferred embodiment, step (c-1) is carried out in a vacuum state, preferably in a vacuum of 0 to 900 mbar, more preferably in a vacuum of 1 to 500 mbar, and in a range of 10 to 200. Vacuum is preferred.

較佳地，於根據本發明之方法中，步驟(c-1)係於0至60℃之溫度範圍中進行，以10℃至50℃較佳，以20至40℃更佳。 Preferably, in the method according to the present invention, the step (c-1) is carried out in a temperature range of from 0 to 60 ° C, preferably from 10 ° C to 50 ° C, more preferably from 20 to 40 ° C.

於另一較佳實施例中，其方法包括以下步驟：(a-2)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽以溶媒溶解。 In another preferred embodiment, the method comprises the steps of: (a-2) (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9' -Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride was dissolved in a solvent.

較佳地，該溶媒係選自由二氯甲烷、N-甲基-2-吡咯啶酮、甲醇、二甲基甲醯胺與其混合物組成之群組。 Preferably, the solvent is selected from the group consisting of dichloromethane, N-methyl-2-pyrrolidone, methanol, dimethylformamide, and mixtures thereof.

於一特佳實施例中，其有機溶媒為二氯甲烷與甲醇之混合物。較 佳地，二氯甲烷與甲醇之比例係介於10：1至1：10之範圍之間，以7：1至1：5之範圍更佳，以6：1至1：3之範圍又更佳，以5：1至1：1之範圍再更佳，以4：1至2：1之範圍最佳，以3.5：1至2.5：1之範圍為首選(體積/體積比)。 In a particularly preferred embodiment, the organic solvent is a mixture of dichloromethane and methanol. More Preferably, the ratio of dichloromethane to methanol is between 10:1 and 1:10, more preferably in the range of 7:1 to 1:5, and in the range of 6:1 to 1:3. Preferably, it is better in the range of 5:1 to 1:1, and the range of 4:1 to 2:1 is the best, and the range of 3.5:1 to 2.5:1 is preferred (volume/volume ratio).

較佳地，於根據本發明之方法中，步驟(a-2)係於相應溶媒之沸點或較低之溫度中進行，以不高於80℃之溫度較佳，以不高於60℃更佳，以不高於40℃又更佳，以20至40℃之溫度範圍為首選。 Preferably, in the method according to the present invention, the step (a-2) is carried out at a boiling point or a lower temperature of the corresponding solvent, preferably at a temperature not higher than 80 ° C, and more preferably not higher than 60 ° C. Preferably, it is preferably not higher than 40 ° C, and the temperature range of 20 to 40 ° C is preferred.

於一較佳實施例中，根據本發明之方法另包括以下步驟：(b-2)將於步驟(a-2)得到之溶液中之溶媒蒸發。 In a preferred embodiment, the method according to the invention further comprises the step of: (b-2) evaporating the solvent in the solution obtained in step (a-2).

適用於蒸發溶媒之方法已為熟知此技術領域者所知。較佳地，於根據本發明之方法中，溶媒係於空氣、空氣氣流或惰性氣體氣流中蒸發，特別是氬氣或氮氣氣流。然而，亦可於真空狀態蒸發溶媒，例如使用旋轉蒸發器。 Suitable methods for evaporating the solvent are known to those skilled in the art. Preferably, in the process according to the invention, the solvent is vaporized in a stream of air, air or inert gas, in particular an argon or nitrogen stream. However, it is also possible to evaporate the solvent in a vacuum state, for example using a rotary evaporator.

較佳地，於根據本發明之方法中，溶媒係於室溫蒸發。 Preferably, in the process according to the invention, the solvent is evaporated at room temperature.

於另一較佳實施例中，其方法另包括以下步驟：(b-2')將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽從由步驟(a-2)得到之溶液中沉澱出。 In another preferred embodiment, the method further comprises the step of: (b-2')-(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4', 9'-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride from the step (a-2) Precipitated in the solution.

適用之沉澱方法已為熟知此技術領域者所知。於根據本發明之方法中，可藉由降低由步驟(a-2)得到之溶液之體積及/或將該溶液冷卻進行步驟(b-2')，以冷卻至最高15℃之溫度較佳，以最高10℃更佳，以最高4至8℃最佳，及/或藉由將該溶液冷卻，以冷卻至較根據步驟(a-2)之溫度低至少10℃之溫度較佳，以至少低30℃更佳，以至少低60℃又更佳。 Suitable precipitation methods are known to those skilled in the art. In the method according to the present invention, it is preferred to cool to a temperature of up to 15 ° C by lowering the volume of the solution obtained in the step (a-2) and/or cooling the solution to carry out the step (b-2'). More preferably at a maximum of 10 ° C, preferably at a maximum of 4 to 8 ° C, and/or by cooling the solution to a temperature of at least 10 ° C lower than the temperature according to step (a-2), preferably It is preferably at least 30 ° C lower, and more preferably at least 60 ° C lower.

於一較佳實施例中，步驟(b-2')係藉由添加介質進行，於該介質中，(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’- 吡喃並-[3,4,b]吲哚]-4-胺鹽酸鹽於步驟(a-2)得到之溶液中僅有極低之溶解度(「反溶劑(anti-solvent)」)。該介質以選自由酯類，如乙酸乙酯、乙酸正丙酯、乙酸異丙酯、乙酸正丁酯與乙酸異丁酯；醚類，例如於甲基叔丁基醚、二***與二異丙醚；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；腈類，例如乙腈；啶、乙酸與水組成之群組較佳。 In a preferred embodiment, step (b-2') is carried out by adding a medium in which (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl -4',9'-dihydro-3'H-spiro [cyclohexane-1,1'- The pyrido-[3,4,b]indole-4-amine hydrochloride has only a very low solubility ("anti-solvent") in the solution obtained in step (a-2). The medium is selected from the group consisting of esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; ethers such as methyl t-butyl ether, diethyl ether and diiso Propyl ether; ketones such as acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one and hexan-3-one; nitriles such as acetonitrile; pyridine, acetic acid and water The group is preferred.

特佳者為甲基叔丁基醚與二***。 Particularly preferred are methyl tert-butyl ether and diethyl ether.

對(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低溶解度之介質、沉澱劑或反溶劑之用量選擇，以可使溶解成分於添加後即開始沉澱較佳。 (1r,4r)-6'-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyridyl The argon [3,4,b]吲哚]-4-amine hydrochloride is selected only in the amount of a medium having a very low solubility, a precipitant or an anti-solvent, so that the dissolved component starts to precipitate immediately after the addition.

亦可將對(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低溶解度之介質之總量分成數個份量，以分成2或3個份量較佳。於此實施例中，溶解成分以於添加最後一份量後開始沉澱較佳。 (1r,4r)-6'-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1 The total amount of '-pyrano[3,4,b]吲哚]-4-amine hydrochloride which has only a very low solubility medium is divided into several parts, preferably divided into 2 or 3 parts. In this embodiment, it is preferred to dissolve the ingredients to initiate precipitation after the last amount is added.

溶解成分之沉澱反應，以添加沉澱劑後立即開始，以添加沉澱劑總量之後較佳，或者延遲2秒至120分鐘之後開始較佳。較佳地，溶解成分之沉澱反應以於最久60分鐘之期間內開始較佳，以最久30分鐘內更佳，以最久20分鐘內又更佳，以最久10分鐘內再更佳，以最久5分鐘內最佳，以最久3分鐘內為首選。 The precipitation reaction of the dissolved components is started immediately after the addition of the precipitating agent, preferably after the total amount of the precipitating agent is added, or after a delay of 2 seconds to 120 minutes. Preferably, the precipitation reaction of the dissolved components starts better during the longest period of 60 minutes, preferably in the longest 30 minutes, preferably in the longest 20 minutes, and preferably in the longest 10 minutes. , the best in the longest 5 minutes, the first choice within 3 minutes.

較佳地，於根據本發明之方法中，步驟(b-2)或(b-2')後之所有步驟係係分別以介於40與0℃之間之溫度進行，以介於35與5℃之間更佳，以介於25與15℃之間又更佳。 Preferably, in the method according to the invention, all the steps after step (b-2) or (b-2') are carried out at a temperature between 40 and 0 ° C, respectively, to More preferably between 5 ° C and even better between 25 and 15 ° C.

較佳地，於根據本發明之方法中，於步驟(b-2')得到之懸浮液係經至少1分鐘之攪拌，以至少2分鐘較佳，以至少3分鐘更佳，以至少5分鐘最佳。 Preferably, in the method according to the present invention, the suspension obtained in the step (b-2') is stirred for at least 1 minute, preferably at least 2 minutes, more preferably at least 3 minutes, and at least 5 minutes. optimal.

較佳地，根據本發明之方法另包括以下步驟： (c-2')分離，以將於步驟(b-2')得到之沉澱物過濾出較佳。 Preferably, the method according to the invention further comprises the following steps: (c-2') is separated, preferably by filtering the precipitate obtained in the step (b-2').

較佳地，根據本發明之方法另包括以下步驟：(d-2')將由步驟(c-2')得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (d-2') drying the solid obtained from step (c-2').

於一較佳實施例中，步驟(d-2')係於空氣或惰性氣體氣流中進行，例如氬氣或氮氣氣流。 In a preferred embodiment, step (d-2') is carried out in a stream of air or an inert gas, such as an argon or nitrogen stream.

於另一較佳實施例中，步驟(c-1)係於真空狀態進行，以0至900 mbar之真空狀態更佳，以1至500 mbar之真空狀態又更佳，以10至200 mbar之真空狀態特佳。 In another preferred embodiment, step (c-1) is carried out in a vacuum state, preferably in a vacuum of 0 to 900 mbar, more preferably in a vacuum of 1 to 500 mbar, and in a range of 10 to 200 mbar. The vacuum condition is particularly good.

本發明另一方面涉及利用上述方法獲得之晶形D。 Another aspect of the invention relates to a crystalline form D obtained by the above method.

本發明另一方面涉及晶形E(同素異形體E)。 Another aspect of the invention relates to Form E (homomorphism E).

較佳地，根據本發明之晶形D具有一個或更多個選自由9.1±0.2(2Θ)、17.1±0.2(2Θ)、17.7±0.2(2Θ)、19.6±0.2(2Θ)、21.3±0.2(2Θ)、22.5±0.2(2Θ)、23.6±0.2(2Θ)、24.6±0.2(2Θ)與28.8±0.2(2Θ)等X光繞射波峰組成之群組。於數個較佳實施例中，其晶形包含位於17.1±0.2(2Θ)、17.7±0.2(2Θ)與19.6±0.2(2Θ)之X光繞射波峰。於數個較佳實施例中，其晶形包含一位於19.6±0.2(2Θ)之X光繞射波峰。 Preferably, the crystal form D according to the present invention has one or more selected from the group consisting of 9.1 ± 0.2 (2 Θ), 17.1 ± 0.2 (2 Θ), 17.7 ± 0.2 (2 Θ), 19.6 ± 0.2 (2 Θ), 21.3 ± 0.2 ( 2Θ), 22.5±0.2 (2Θ), 23.6±0.2 (2Θ), 24.6±0.2 (2Θ) and 28.8±0.2 (2Θ) and other groups of X-ray diffraction peaks. In several preferred embodiments, the crystalline form comprises X-ray diffraction peaks at 17.1 ± 0.2 (2 Θ), 17.7 ± 0.2 (2 Θ), and 19.6 ± 0.2 (2 Θ). In several preferred embodiments, the crystal form comprises a X-ray diffraction peak at 19.6 ± 0.2 (2 Å).

於數個較佳實施例中，晶形E包含位於9.1±0.2(2Θ)、17.1±0.2(2Θ)、17.7±0.2(2Θ)、19.6±0.2(2Θ)、21.3±0.2(2Θ)、22.5±0.2(2Θ)、23.6±0.2(2Θ)、24.6±0.2(2Θ)，及選擇性地28.8±0.2(2Θ)之X光繞射波峰。 In several preferred embodiments, Form E is comprised of 9.1 ± 0.2 (2 Θ), 17.1 ± 0.2 (2 Θ), 17.7 ± 0.2 (2 Θ), 19.6 ± 0.2 (2 Θ), 21.3 ± 0.2 (2 Θ), 22.5 ± 0.2 (2 Θ), 23.6 ± 0.2 (2 Θ), 24.6 ± 0.2 (2 Θ), and optionally 28.8 ± 0.2 (2 Θ) X-ray diffraction peaks.

根據本發明之晶形E之特徵可為其進一步具有至少一個選自由18.3±0.2(2Θ)、23.4±0.2(2Θ)、24.1±0.2(2Θ)、26.2±0.2(2Θ)、26.8±0.2(2Θ)、30.5±0.2(2Θ)與31.7±0.2(2Θ)等X光繞射波峰組成之群組。 The crystal form E according to the present invention may be characterized in that it further has at least one selected from the group consisting of 18.3 ± 0.2 (2 Θ), 23.4 ± 0.2 (2 Θ), 24.1 ± 0.2 (2 Θ), 26.2 ± 0.2 (2 Θ), and 26.8 ± 0.2 (2 Θ). ), a group consisting of 30.5 ± 0.2 (2 Θ) and 31.7 ± 0.2 (2 Θ) and other X-ray diffraction peaks.

此外，根據本發明之晶形E之特徵可為其具有一個或更多個選自由9.1±0.2(2Θ)、17.1±0.2(2Θ)、17.7±0.2(2Θ)、19.6±0.2(2Θ)、21.3±0.2(2Θ)、22.5±0.2(2Θ)、23.6±0.2(2Θ)、24.6±0.2(2Θ)與28.8±0.2(2Θ) 等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由18.3±0.2(2Θ)、23.4±0.2(2Θ)、24.1±0.2(2Θ)、26.2±0.2(2Θ)、26.8±0.2(2Θ)、30.5±0.2(2Θ)與31.7±0.2(2Θ)等X光繞射波峰組成之群組，其額外具有至少一個選自由15.7±0.2(2Θ)、18.9±0.2(2Θ)、20.7±0.2(2Θ)、25.1±0.2(2Θ)、27.8±0.2(2Θ)、30.2±0.2(2Θ)與34.8±0.2(2Θ)等X光繞射波峰組成之群組。 Further, the crystal form E according to the present invention may be characterized in that it has one or more selected from the group consisting of 9.1 ± 0.2 (2 Θ), 17.1 ± 0.2 (2 Θ), 17.7 ± 0.2 (2 Θ), 19.6 ± 0.2 (2 Θ), 21.3. ±0.2(2Θ), 22.5±0.2(2Θ), 23.6±0.2(2Θ), 24.6±0.2(2Θ) and 28.8±0.2(2Θ) a group of X-ray diffraction peaks, and optionally one or more selected from the group consisting of 18.3 ± 0.2 (2 Θ), 23.4 ± 0.2 (2 Θ), 24.1 ± 0.2 (2 Θ), 26.2 ± 0.2 (2 Θ), a group consisting of 26.8±0.2 (2Θ), 30.5±0.2 (2Θ) and 31.7±0.2 (2Θ) and other X-ray diffraction peaks, which additionally have at least one selected from the group consisting of 15.7±0.2 (2Θ) and 18.9±0.2 (2Θ) ), a group consisting of 20.7±0.2 (2Θ), 25.1±0.2 (2Θ), 27.8±0.2 (2Θ), 30.2±0.2 (2Θ) and 34.8±0.2 (2Θ) and other X-ray diffraction peaks.

根據本發明之晶形E之特徵可為其進一步具有一個或更多個選自由9.1±0.2(2Θ)、17.1±0.2(2Θ)、17.7±0.2(2Θ)、19.6±0.2(2Θ)、21.3±0.2(2Θ)、22.5±0.2(2Θ)、23.6±0.2(2Θ)、24.6±0.2(2Θ)與28.8±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由18.3±0.2(2Θ)、23.4±0.2(2Θ)、24.1±0.2(2Θ)、26.2±0.2(2Θ)、26.8±0.2(2Θ)、30.5±0.2(2Θ)與31.7±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由15.7±0.2(2Θ)、18.9±0.2(2Θ)、20.7±0.2(2Θ)、25.1±0.2(2Θ)、27.8±0.2(2Θ)、30.2±0.2(2Θ)與34.8±0.2(2Θ)等X光繞射波峰組成之群組，其額外具有至少一個選自由8.1±0.2(2Θ)、10.6±0.2(2Θ)、11.2±0.2(2Θ)、11.6±0.2(2Θ)與13.3±0.2(2Θ)等X光繞射波峰組成之群組。 The crystal form E according to the present invention may be further characterized by having one or more selected from the group consisting of 9.1 ± 0.2 (2 Θ), 17.1 ± 0.2 (2 Θ), 17.7 ± 0.2 (2 Θ), 19.6 ± 0.2 (2 Θ), 21.3 ± a group consisting of 0.2 (2 Θ), 22.5 ± 0.2 (2 Θ), 23.6 ± 0.2 (2 Θ), 24.6 ± 0.2 (2 Θ), and 28.8 ± 0.2 (2 Θ) X-ray diffraction peaks, and optionally one or more The plurality selected from the group consisting of 18.3 ± 0.2 (2 Θ), 23.4 ± 0.2 (2 Θ), 24.1 ± 0.2 (2 Θ), 26.2 ± 0.2 (2 Θ), 26.8 ± 0.2 (2 Θ), 30.5 ± 0.2 (2 Θ) and 31.7 ± 0.2 ( 2Θ) a group of X-ray diffraction peaks, and optionally one or more selected from the group consisting of 15.7 ± 0.2 (2 Θ), 18.9 ± 0.2 (2 Θ), 20.7 ± 0.2 (2 Θ), 25.1 ± 0.2 (2 Θ a group of X-ray diffraction peaks such as 27.8 ± 0.2 (2 Θ), 30.2 ± 0.2 (2 Θ), and 34.8 ± 0.2 (2 Θ), which additionally have at least one selected from the group consisting of 8.1 ± 0.2 (2 Θ), 10.6 ± 0.2 (2Θ), 11.2±0.2 (2Θ), 11.6±0.2 (2Θ) and 13.3±0.2 (2Θ) and other groups of X-ray diffraction peaks.

所有2Θ值係指利用波長為1.54060 Å之CuKα輻射所測得之X射線繞射圖。 All 2 Θ values refer to X-ray diffraction patterns measured using CuKα radiation at a wavelength of 1.54060 Å.

根據本發明之晶形E之特徵可為其進一步具有一個或更多個選自由1569±2 cm-1、2963±2 cm-1與3069±2 cm-1等拉曼光譜帶組成之群組。 The crystal form E according to the present invention may be characterized in that it further has one or more groups selected from the group consisting of Raman spectral bands of 1569 ± 2 cm -1 , 2963 ± 2 cm -1 and 3069 ± 2 cm -1 .

根據本發明之晶形E之特徵可為其進一步具有一個或更多個選自由1569±2 cm-1、2963±2 cm-1與3069±2 cm-1等拉曼光譜帶組成之群組；及/或一個或更多個選自由160±2 cm-1、176±2 cm-1、686±2 cm-1、836±2 cm-1、917±2 cm-1、1003±2 cm-1、1299±2 cm-1、1308±2 cm-1 與1582±2 cm-1等拉曼光譜帶組成之群組；及/或一個或更多個選自由211±2 cm-1、253±2 cm-1、369±2 cm-1、491±2 cm-1、599±2 cm-1、1029±2 cm-1、1200±2 cm-1、1220±2 cm-1、1376±2 cm-1、1441±2 cm-1、1465±2 cm-1、2855±2 cm-1、2873±2 cm-1、2889±2 cm-1、2986±2 cm-1與3048±2 cm-1等拉曼光譜帶組成之群組。 The crystal form E according to the present invention may be characterized in that it further has one or more groups selected from the group consisting of Raman spectral bands of 1569 ± 2 cm -1 , 2963 ± 2 cm -1 and 3069 ± 2 cm -1 ; And / or one or more selected from the group consisting of 160 ± 2 cm -1 , 176 ± 2 cm -1 , 686 ± 2 cm -1 , 836 ± 2 cm -1 , 917 ± 2 cm -1 , 1003 ± 2 cm - 1 , a group consisting of 1299 ± 2 cm -1 , 1308 ± 2 cm -1 and 1582 ± 2 cm -1 and other Raman spectral bands; and / or one or more selected from 211 ± 2 cm -1 , 253 ±2 cm -1 , 369 ± 2 cm -1 , 491 ± 2 cm -1 , 599 ± 2 cm -1 , 1029 ± 2 cm -1 , 1200 ± 2 cm -1 , 1220 ± 2 cm -1 , 1376 ± 2 cm -1 , 1441 ± 2 cm -1 , 1465 ± 2 cm -1 , 2855 ± 2 cm -1 , 2873 ± 2 cm -1 , 2889 ± 2 cm -1 , 2986 ± 2 cm -1 and 3048 ± 2 A group consisting of a Raman spectral band such as cm -1 .

根據本發明之晶形E之特徵可為其進一步具有一個或更多個選自由287±2 cm-1、317±2 cm-1、395±2 cm-1、433±2 cm-1、471±2 cm-1、517±2 cm-1、538±2 cm-1、558±2 cm-1、568±2 cm-1、619±2 cm-1、629±2 cm-1、676±2 cm-1、713±2 cm-1、786±2 cm-1、854±2 cm-1、870±2 cm-1、889±2 cm-1、952±2 cm-1、983±2 cm-1、993±2 cm-1、1019±2 cm-1、1047±2 cm-1、1076±2 cm-1、1107±2 cm-1、1117±2 cm-1、1133±2 cm-1、1142±2 cm-1、1166±2 cm-1、1267±2 cm-1、1353±2 cm-1、1494±2 cm-1、1630±2 cm-1與3031±2 cm-1等拉曼光譜帶組成之群組。 The crystal form E according to the present invention may be further characterized by having one or more selected from the group consisting of 287±2 cm -1 , 317 ± 2 cm -1 , 395 ± 2 cm -1 , 433 ± 2 cm -1 , 471 ± 2 cm -1 , 517 ± 2 cm -1 , 538 ± 2 cm -1 , 558 ± 2 cm -1 , 568 ± 2 cm -1 , 619 ± 2 cm -1 , 629 ± 2 cm -1 , 676 ± 2 Cm -1 , 713 ± 2 cm -1 , 786 ± 2 cm -1 , 854 ± 2 cm -1 , 870 ± 2 cm -1 , 889 ± 2 cm -1 , 952 ± 2 cm -1 , 983 ± 2 cm -1 , 993 ± 2 cm -1 , 1019 ± 2 cm -1 , 1047 ± 2 cm -1 , 1076 ± 2 cm -1 , 1107 ± 2 cm -1 , 1117 ± 2 cm -1 , 1133 ± 2 cm - 1 , 1142 ± 2 cm -1 , 1166 ± 2 cm -1 , 1267 ± 2 cm -1 , 1353 ± 2 cm -1 , 1494 ± 2 cm -1 , 1630 ± 2 cm -1 and 3031 ± 2 cm -1 A group of equal Raman spectral bands.

本發明另一方面涉及一種製備上述晶形E之方法，其包括以下步驟：(a-1)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽由自由鹼溶液或懸浮液中沉澱出。 Another aspect of the invention relates to a process for the preparation of the above Form E, which comprises the steps of: (a-1) (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4 ',9'-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride from free base solution or suspension Precipitated in the middle.

該溶液或懸浮液以包含1,4-二氧陸圜較佳。較佳地，以該溶液或懸浮液所含之溶媒總體積計，該溶液或懸浮液之1,4-二氧陸圜含量為至少5體積百分比，以至少30體積百分比更佳，以至少50體積百分比又更佳，以至少80體積百分比再更佳，以至少90體積百分比最佳，以至少95體積百分比為首選。特佳地，1,4-二氧陸圜為該溶液或懸浮液所含之唯一溶媒。 Preferably, the solution or suspension is comprised of 1,4-dioxane. Preferably, the solution or suspension has a 1,4-dioxane content of at least 5 volume percent based on the total volume of the solvent contained in the solution or suspension, more preferably at least 30 volume percent, and at least 50 The volume percentage is more preferably, more preferably at least 80 volume percent, most preferably at least 90 volume percent, and preferably at least 95 volume percent. Particularly preferably, 1,4-dioxane is the sole solvent contained in the solution or suspension.

可藉由添加氯化氫進行步驟(a-1)。 Step (a-1) can be carried out by adding hydrogen chloride.

於一較佳實施例中，所添加之氯化氫為氯化氫氣之形式。 In a preferred embodiment, the hydrogen chloride added is in the form of hydrogen chloride.

於另一較佳實施例中，氯化氫係藉由進行反應之方式原位生成，例如藉由於一水性溶液中添加三甲基氯矽烷。 In another preferred embodiment, hydrogen chloride is formed in situ by reaction, for example by the addition of trimethylchlorodecane to an aqueous solution.

於又另一較佳實施例中，氯化氫為液體形式。較佳地，該溶液為一溶於有機溶媒之氯化氫溶液，以1,4-二氧陸圜為首選。 In yet another preferred embodiment, the hydrogen chloride is in liquid form. Preferably, the solution is a hydrogen chloride solution dissolved in an organic solvent, and 1,4-dioxane is preferred.

較佳地，該溶液所含之氯化氫濃度係介於0.01 mol/L至15 mol/L之範圍，以0.02 mol/L至12.5 mol/L之範圍更佳，以0.05 mol/L至10 mol/L之範圍又更佳，以0.1 mol/L至7.5 mol/L之範圍再更佳，以0.2 mol/L至10 mol/L之範圍最佳，以0.3 mol/L至5 mol/L之範圍為首選。 Preferably, the concentration of hydrogen chloride contained in the solution is in the range of 0.01 mol/L to 15 mol/L, more preferably in the range of 0.02 mol/L to 12.5 mol/L, and 0.05 mol/L to 10 mol/ The range of L is better, preferably in the range of 0.1 mol/L to 7.5 mol/L, preferably in the range of 0.2 mol/L to 10 mol/L, and in the range of 0.3 mol/L to 5 mol/L. For the first choice.

較佳地，添加於該自由鹼溶液或懸浮液之氯化氫量為莫耳過剩量。 Preferably, the amount of hydrogen chloride added to the free base solution or suspension is a molar excess.

較佳地，於根據本發明之方法中，步驟(a-1)係於相應溶媒之沸點或較低之溫度中進行，以不高於80℃之溫度較佳，以不高於60℃更佳，以不高於40℃又更佳，以20至40℃之溫度範圍為首選。 Preferably, in the method according to the present invention, the step (a-1) is carried out at a boiling point or a lower temperature of the corresponding solvent, preferably at a temperature not higher than 80 ° C, and more preferably not higher than 60 ° C. Preferably, it is preferably not higher than 40 ° C, and the temperature range of 20 to 40 ° C is preferred.

較佳地，於步驟(a-1)得到之懸浮液係經最久1天之攪拌，以最久4小時較佳，以最久60分鐘更佳，以最久30分鐘又更佳，以最久20分鐘再更佳，以最久15分鐘最佳，以最久10分鐘為首選。 Preferably, the suspension obtained in the step (a-1) is stirred for a maximum of one day, preferably for a maximum of 4 hours, preferably for a maximum of 60 minutes, and more preferably for a maximum of 30 minutes. The longest time is 20 minutes, the best is 15 minutes, and the longest 10 minutes is the first choice.

較佳地，根據本發明之方法另包括以下步驟：(b-1)分離，以將於步驟(a-1)得到之固體過濾出較佳。 Preferably, the method according to the invention further comprises the step of: (b-1) separating, preferably filtering the solid obtained in step (a-1).

較佳地，根據本發明之方法另包括以下步驟：(c-1)將由步驟(b-1)得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (c-1) drying the solid obtained from step (b-1).

較佳地，步驟(c-1)係於空氣或惰性氣體氣流中進行，例如氫氣或氮氣氣流。 Preferably, step (c-1) is carried out in a stream of air or an inert gas, such as a stream of hydrogen or nitrogen.

本發明另一方面涉及一利用上述方法獲得之晶形E。 Another aspect of the invention relates to a crystal form E obtained by the above method.

本發明另一方面涉及晶形F。 Another aspect of the invention relates to Form F.

較佳地，根據本發明之晶形F具有一個或更多個選自由11.5±0.2(2Θ)、14.5±0.2(2Θ)、18.5±0.2(2Θ)、19.3±0.2(2Θ)、27.3±0.2(2Θ)與29.1±0.2(2Θ)等X光繞射波峰組成之群組。於數個較佳實施例中， 其晶形包含位於19.3±0.2(2Θ)與29.1±0.2(2Θ)之X光繞射波峰。於數個較佳實施例中，其晶形包含一位於19.3±0.2(2Θ)之X光繞射波峰。 Preferably, the crystalline form F according to the present invention has one or more selected from the group consisting of 11.5 ± 0.2 (2 Θ), 14.5 ± 0.2 (2 Θ), 18.5 ± 0.2 (2 Θ), 19.3 ± 0.2 (2 Θ), 27.3 ± 0.2 ( 2Θ) A group consisting of X-ray diffraction peaks such as 29.1±0.2 (2Θ). In several preferred embodiments, Its crystal form contains X-ray diffraction peaks at 19.3 ± 0.2 (2 Θ) and 29.1 ± 0.2 (2 Θ). In several preferred embodiments, the crystal form comprises an X-ray diffraction peak at 19.3 ± 0.2 (2 Å).

於數個較佳實施例中，晶形F包含位於14.5±0.2(2Θ)、18.5±0.2(2Θ)、19.3±0.2(2Θ)、27.3±0.2(2Θ)、29.1±0.2(2Θ)及選擇性11.5±0.2(2Θ)之X光繞射波峰。 In several preferred embodiments, Form F comprises 14.5 ± 0.2 (2 Θ), 18.5 ± 0.2 (2 Θ), 19.3 ± 0.2 (2 Θ), 27.3 ± 0.2 (2 Θ), 29.1 ± 0.2 (2 Θ), and selectivity. X-ray diffraction peak of 11.5 ± 0.2 (2 Θ).

根據本發明之晶形F可額外具有至少一個選自由21.2±0.2(2Θ)、22.0±0.2(2Θ)、27.5±0.2(2Θ)、30.3±0.2(2Θ)與31.7±0.2(2Θ)等X光繞射波峰組成之群組。 The crystal form F according to the present invention may additionally have at least one X-ray selected from the group consisting of 21.2 ± 0.2 (2 Θ), 22.0 ± 0.2 (2 Θ), 27.5 ± 0.2 (2 Θ), 30.3 ± 0.2 (2 Θ), and 31.7 ± 0.2 (2 Θ). A group of diffracted peaks.

此外，根據本發明之晶形F之特徵可為其具有一個或更多個選自由11.5±0.2(2Θ)、14.5±0.2(2Θ)、18.5±0.2(2Θ)、19.3±0.2(2Θ)、27.3±0.2(2Θ)與29.1±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由21.2±0.2(2Θ)、22.0±0.2(2Θ)、27.5±0.2(2Θ)、30.3±0.2(2Θ)與31.7±0.2(2Θ)等X光繞射波峰組成之群組，其額外具有至少一個選自由16.1±0.2(2Θ)、16.6±0.2(2Θ)、19.9±0.2(2Θ)、20.5±0.2(2Θ)、23.2±0.2(2Θ)、26.1±0.2(2Θ)、26.5±0.2(2Θ)與30.7±0.2(2Θ)等X光繞射波峰組成之群組。 Further, the crystal form F according to the present invention may be characterized by having one or more selected from the group consisting of 11.5 ± 0.2 (2 Θ), 14.5 ± 0.2 (2 Θ), 18.5 ± 0.2 (2 Θ), 19.3 ± 0.2 (2 Θ), 27.3. a group consisting of ±0.2 (2Θ) and 29.1±0.2 (2Θ) and other X-ray diffraction peaks, and optionally one or more selected from 21.2±0.2(2Θ), 22.0±0.2(2Θ), 27.5± a group consisting of 0.2 (2 ±), 30.3 ± 0.2 (2 Θ), and 31.7 ± 0.2 (2 Θ), etc., which additionally has at least one selected from the group consisting of 16.1 ± 0.2 (2 Θ), 16.6 ± 0.2 (2 Θ), Groups of X-ray diffraction peaks such as 19.9±0.2(2Θ), 20.5±0.2(2Θ), 23.2±0.2(2Θ), 26.1±0.2(2Θ), 26.5±0.2(2Θ) and 30.7±0.2(2Θ) group.

根據本發明之晶形F之特徵可為其進一步具有一個或更多個選自由11.5±0.2(2Θ)、14.5±0.2(2Θ)、18.5±0.2(2Θ)、19.3±0.2(2Θ)、27.3±0.2(2Θ)與29.1±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由21.2±0.2(2Θ)、22.0±0.2(2Θ)、27.5±0.2(2Θ)、30.3±0.2(2Θ)and 31.7±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由16.1±0.2(2Θ)、16.6±0.2(2Θ)、19.9±0.2(2Θ)、20.5±0.2(2Θ)、23.2±0.2(2Θ)、26.1±0.2(2Θ)、26.5±0.2(2Θ)與30.7±0.2(2Θ)等X光繞射波峰組成之群組，其額外具有至少一個選自由9.9±0.2(2Θ)、10.5±0.2(2Θ)、17.4±0.2(2Θ)、24.5±0.2(2Θ)、28.2±0.2(2Θ)、32.0±0.2(2Θ)、33.0±0.2(2Θ)與34.6±0.2(2Θ)等X光繞射波峰 組成之群組。 The crystal form F according to the present invention may be further characterized by having one or more selected from the group consisting of 11.5 ± 0.2 (2 Θ), 14.5 ± 0.2 (2 Θ), 18.5 ± 0.2 (2 Θ), 19.3 ± 0.2 (2 Θ), 27.3 ± a group consisting of 0.2 (2 Θ) and 29.1 ± 0.2 (2 Θ) X-ray diffraction peaks, and optionally one or more selected from 21.2 ± 0.2 (2 Θ), 22.0 ± 0.2 (2 Θ), 27.5 ± 0.2 a group consisting of (2Θ), 30.3±0.2 (2Θ), and 31.7±0.2 (2Θ), such as X-ray diffraction peaks, and optionally one or more selected from 16.1±0.2(2Θ), 16.6±0.2 ( 2Θ), 19.9±0.2 (2Θ), 20.5±0.2 (2Θ), 23.2±0.2 (2Θ), 26.1±0.2 (2Θ), 26.5±0.2 (2Θ) and 30.7±0.2(2Θ) X-ray diffraction peaks a group consisting of at least one selected from the group consisting of 9.9 ± 0.2 (2 Θ), 10.5 ± 0.2 (2 Θ), 17.4 ± 0.2 (2 Θ), 24.5 ± 0.2 (2 Θ), 28.2 ± 0.2 (2 Θ), 32.0 ± 0.2 (2Θ), 33.0±0.2 (2Θ) and 34.6±0.2 (2Θ) X-ray diffraction peaks The group that makes up.

所有2Θ值係指利用波長為1.54060 Å之CuKα輻射所測得之X射線繞射圖。 All 2 Θ values refer to X-ray diffraction patterns measured using CuKα radiation at a wavelength of 1.54060 Å.

根據本發明之晶形F之特徵可為其進一步具有一個或更多個選自由160±2 cm-1、1295±2 cm-1、1573±2 cm-1、1585±2 cm-1、2979±2 cm-1與3070±2 cm-1等拉曼光譜帶組成之群組。 The crystal form F according to the present invention may be further characterized by having one or more selected from the group consisting of 160±2 cm -1 , 1295±2 cm -1 , 1573±2 cm -1 , 1585±2 cm -1 , 2979± A group consisting of 2 cm -1 and 3070 ± 2 cm -1 Raman spectral bands.

根據發明之晶形F之特徵可為其進一步具有一個或更多個選自由160±2 cm-1、1295±2 cm-1、1573±2 cm-1、1585±2 cm-1、2979±2 cm-1 and 3070±2 cm-1等拉曼光譜帶組成之群組；及/或一個或更多個選自由174±2 cm-1、206±2 cm-1、917±2 cm-1、1003±2 cm-1與2954±2 cm-1等拉曼光譜帶組成之群組；及/或一個或更多個選自由254±2 cm-1、598±2 cm-1、683±2 cm-1、1030±2 cm-1、1110±2 cm-1、1217±2 cm-1、1434±2 cm-1、1458±2 cm-1、1468±2 cm-1、2895±2 cm-1、2942±2 cm-1與3029±2 cm-1等拉曼光譜帶組成之群組。 The crystal form F according to the invention may further have one or more selected from the group consisting of 160±2 cm -1 , 1295±2 cm -1 , 1573±2 cm -1 , 1585±2 cm -1 , 2979±2 a group consisting of a Raman spectral band such as cm -1 and 3070 ± 2 cm -1 ; and / or one or more selected from the group consisting of 174 ± 2 cm -1 , 206 ± 2 cm -1 , and 917 ± 2 cm -1 a group consisting of Raman spectral bands such as 1003 ± 2 cm -1 and 2954 ± 2 cm -1 ; and / or one or more selected from the group consisting of 254 ± 2 cm -1 , 598 ± 2 cm -1 , 683 ± 2 cm -1 , 1030 ± 2 cm -1 , 1110 ± 2 cm -1 , 1217 ± 2 cm -1 , 1434 ± 2 cm -1 , 1458 ± 2 cm -1 , 1468 ± 2 cm -1 , 2895 ± 2 A group consisting of a Raman spectral band such as cm -1 , 2942 ± 2 cm -1 and 3029 ± 2 cm -1 .

根據本發明之晶形F之特徵可為其進一步具有一個或更多個選自由273±2 cm-1、367±2 cm-1、390±2 cm-1、436±2 cm-1、488±2 cm-1、515±2 cm-1、538±2 cm-1、568±2 cm-1、620±2 cm-1、707±2 cm-1、769±2 cm-1、786±2 cm-1、829±2 cm-1、888±2 cm-1、980±2 cm-1、1047±2 cm-1、1132±2 cm-1、1170±2 cm-1、1201±2 cm-1、1264±2 cm-1、1368±2 cm-1、1486±2 cm-1、1629±2 cm-1與2840±2 cm-1等拉曼光譜帶組成之群組。 The crystal form F according to the present invention may further have one or more selected from the group consisting of 273±2 cm -1 , 367±2 cm -1 , 390±2 cm -1 , 436±2 cm -1 , 488 ± 2 cm -1 , 515 ± 2 cm -1 , 538 ± 2 cm -1 , 568 ± 2 cm -1 , 620 ± 2 cm -1 , 707 ± 2 cm -1 , 769 ± 2 cm -1 , 786 ± 2 Cm -1 , 829 ± 2 cm -1 , 888 ± 2 cm -1 , 980 ± 2 cm -1 , 1047 ± 2 cm -1 , 1132 ± 2 cm -1 , 1170 ± 2 cm -1 , 1201 ± 2 cm -1 , 1264 ± 2 cm -1 , 1368 ± 2 cm -1 , 1486 ± 2 cm -1 , 1629 ± 2 cm -1 and 2840 ± 2 cm -1 and other groups of Raman spectral bands.

本發明另一方面涉及一種如上述製備晶形F之方法，其包括以下步驟：(a-1)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽由自由鹼溶液或懸浮液中沉澱出。 Another aspect of the invention relates to a process for the preparation of Form F as described above, which comprises the steps of: (a-1) (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl- 4',9'-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride from free base solution or suspension Precipitated in the liquid.

較佳地，該溶媒係選自由醇類，例如甲醇、乙醇、正丙醇、異丙醇與正丁醇；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；醚類，例如甲基叔丁基醚、二***、四氫呋喃、二異丙醚與1,4-二氧陸圜；氯化烴，例如二氯甲烷於三氯甲烷，及其混合物組成之群組。 Preferably, the solvent is selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, isopropanol and n-butanol; ketones such as acetone, 2-butanone, pentan-2-one, pent-3- Ketone, hexan-2-one and hexan-3-one; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, diisopropyl ether and 1,4-dioxane; chlorinated hydrocarbons, for example two A group of methyl chloride in chloroform, and mixtures thereof.

較佳地，該溶媒不含水分。 Preferably, the solvent is free of moisture.

可藉由添加氯化氫進行步驟(a-1)。 Step (a-1) can be carried out by adding hydrogen chloride.

於一較佳實施例中，所添加之氯化氫為氯化氫氣之形式。 In a preferred embodiment, the hydrogen chloride added is in the form of hydrogen chloride.

於另一較佳實施例中，氯化氫係藉由進行反應之方式原位生成，例如藉由於一水性溶液中添加三甲基氯矽烷。 In another preferred embodiment, hydrogen chloride is formed in situ by reaction, for example by the addition of trimethylchlorodecane to an aqueous solution.

於又另一較佳實施例中，氯化氫為液體形式。 In yet another preferred embodiment, the hydrogen chloride is in liquid form.

較佳地，該溶液係一溶於有機溶媒之氯化氫溶液，以醇類，例如乙醇、異丙醇與正丁醇為首選。 Preferably, the solution is a hydrogen chloride solution dissolved in an organic solvent, and alcohols such as ethanol, isopropanol and n-butanol are preferred.

較佳地，該溶液所含之氯化氫濃度係介於0.01 mol/L至15 mol/L之範圍之間，以介於0.02 mol/L至12.5 mol/L之範圍更佳，以介於0.05 mol/L至10 mol/L之範圍又更佳，以介於0.1 mol/L至7.5 mol/L之範圍再更佳，以介於0.2 mol/L至10 mol/L之範圍最佳，以介於0.3 mol/L至5 mol/L之範圍為首選。 Preferably, the concentration of hydrogen chloride contained in the solution is between 0.01 mol/L and 15 mol/L, more preferably in the range of 0.02 mol/L to 12.5 mol/L, and is 0.05 mol. The range of /L to 10 mol/L is more preferable, and it is more preferably in the range of 0.1 mol/L to 7.5 mol/L, and is preferably in the range of 0.2 mol/L to 10 mol/L. The range of 0.3 mol/L to 5 mol/L is preferred.

較佳地，添加於該自由鹼溶液或懸浮液之氯化氫量為莫耳過剩量。 Preferably, the amount of hydrogen chloride added to the free base solution or suspension is a molar excess.

較佳地，於根據本發明之方法中，步驟(a-1)係於相應溶媒之沸點或較低之溫度中進行，以不高於80℃之溫度較佳，以不高於60℃之溫度更佳，以不高於40℃又更佳，以20至40℃之溫度範圍為首選。 Preferably, in the method according to the present invention, the step (a-1) is carried out at a boiling point or a lower temperature of the corresponding solvent, preferably at a temperature not higher than 80 ° C, and not higher than 60 ° C. The temperature is better, preferably not higher than 40 ° C, and the temperature range of 20 to 40 ° C is preferred.

較佳地，於根據本發明之方法中，於步驟(a-1)得到之懸浮液係經至少1分鐘之攪拌，以至少2分鐘較佳，以至少3分鐘更佳，以至少5分鐘又更佳，以至少10分鐘再更佳，以至少20分鐘最佳，以至少30分鐘為首選。 Preferably, in the method according to the present invention, the suspension obtained in the step (a-1) is stirred for at least 1 minute, preferably at least 2 minutes, more preferably at least 3 minutes, and at least 5 minutes. More preferably, it is preferably at least 10 minutes, preferably at least 20 minutes, and at least 30 minutes is preferred.

於另一較佳實施例中，於步驟(a-1)得到之懸浮液係經最久1天之攪拌，以最久12小時較佳，以最久6小時更佳，以最久2小時又更佳，以最久60分鐘再更佳，以最久45分鐘最佳，以最久30分鐘為首選。 In another preferred embodiment, the suspension obtained in the step (a-1) is stirred for a maximum of one day, preferably for a maximum of 12 hours, preferably for a maximum of 6 hours, and for a maximum of 2 hours. It is even better, with a maximum of 60 minutes and a better, with a maximum of 45 minutes, with a maximum of 30 minutes as the first choice.

較佳地，根據本發明之方法另包括以下步驟：(b-1)分離，以將於步驟(a-1)得到之固體過濾出較佳。 Preferably, the method according to the invention further comprises the step of: (b-1) separating, preferably filtering the solid obtained in step (a-1).

較佳地，根據本發明之方法另包括以下步驟：(c-1)將由步驟(b-1)得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (c-1) drying the solid obtained from step (b-1).

於一較佳實施例中，步驟(c-1)係於空氣或惰性氣體氣流中進行，例如氬氣或氮氣氣流。 In a preferred embodiment, step (c-1) is carried out in a stream of air or an inert gas, such as an argon or nitrogen stream.

於另一較佳實施例中，步驟(c-1)係於真空狀態進行，以0至900 mbar之真空狀態更佳，以1至500 mbar之真空狀態又更佳，以10至200 mbar之真空狀態為首選。 In another preferred embodiment, step (c-1) is carried out in a vacuum state, preferably in a vacuum of 0 to 900 mbar, more preferably in a vacuum of 1 to 500 mbar, and in a range of 10 to 200 mbar. Vacuum is preferred.

較佳地，於根據本發明之方法中，步驟(c-1)係於0至60℃之溫度範圍中進行，以10至50℃較佳，以20至40℃更佳。 Preferably, in the method according to the present invention, the step (c-1) is carried out in a temperature range of from 0 to 60 ° C, preferably from 10 to 50 ° C, more preferably from 20 to 40 ° C.

於另一較佳實施例中，其方法包括以下步驟：(a-2)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽以一溶媒溶解。 In another preferred embodiment, the method comprises the steps of: (a-2) (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9' -Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride is dissolved in a solvent.

較佳地，該溶媒係選自由二氯甲烷、N-甲基-2-吡咯啶酮、甲醇、二甲基甲醯胺與其混合物組成之群組。 Preferably, the solvent is selected from the group consisting of dichloromethane, N-methyl-2-pyrrolidone, methanol, dimethylformamide, and mixtures thereof.

於一特佳實施例中，其溶媒係二氯甲烷與甲醇之混合物。較佳地，二氯甲烷與甲醇之比例係介於10：1至1：10之間，以介於7：1至1：5之間較佳，以介於6：1至1：3之間更佳，以介於5：1至1：1之間又更佳，以介於4：1至2：1之間最佳，以介於3.5：1至2.5：1之間為首選(體積/體積比)。 In a particularly preferred embodiment, the solvent is a mixture of dichloromethane and methanol. Preferably, the ratio of dichloromethane to methanol is between 10:1 and 1:10, preferably between 7:1 and 1:5, and between 6:1 and 1:3. Better between, better between 5:1 and 1:1, best between 4:1 and 2:1, preferred between 3.5:1 and 2.5:1 ( Volume/volume ratio).

較佳地，於根據本發明之方法中，步驟(a-2)係於相應溶媒之沸點或較低之溫度中進行，以不高於80℃之溫度較佳，以不高於60℃更 佳，以不高於40℃又更佳，以20至40℃之溫度範圍為首選。 Preferably, in the method according to the present invention, the step (a-2) is carried out at a boiling point or a lower temperature of the corresponding solvent, preferably at a temperature not higher than 80 ° C, and more preferably not higher than 60 ° C. Preferably, it is preferably not higher than 40 ° C, and the temperature range of 20 to 40 ° C is preferred.

於一較佳實施例中，其方法包括以下步驟：(b-2)將於步驟(a-2)得到之溶液中之溶媒蒸發。 In a preferred embodiment, the method comprises the steps of: (b-2) evaporating the solvent in the solution obtained in step (a-2).

適用於蒸發溶媒之方法已為熟知此技術領域者所知。較佳地，於根據本發明之方法中，溶媒係於空氣、空氣氣流或惰性氣體氣流中蒸發，特別是氬氣或氮氣氣流。然而，亦可於真空狀態蒸發溶媒，例如使用旋轉蒸發器。 Suitable methods for evaporating the solvent are known to those skilled in the art. Preferably, in the process according to the invention, the solvent is vaporized in a stream of air, air or inert gas, in particular an argon or nitrogen stream. However, it is also possible to evaporate the solvent in a vacuum state, for example using a rotary evaporator.

較佳地，於根據本發明之方法中，溶媒係於室溫蒸發。 Preferably, in the process according to the invention, the solvent is evaporated at room temperature.

於另一較佳實施例中，其方法另包括以下步驟：(b-2')將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽從於步驟(a-2)得到之溶液中沉澱出。 In another preferred embodiment, the method further comprises the step of: (b-2')-(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4', 9'-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride is obtained from step (a-2) Precipitated in the solution.

適用之沉澱方法已為熟知此技術領域者所知。於根據本發明之方法中，可藉由降低由步驟(a-2)得到之溶液之體積及/或將該溶液冷卻進行步驟(b-2')，以冷卻至最高15℃之溫度較佳，以最高10℃更佳，以最高4至8℃最佳，及/或藉由將該溶液冷卻，以冷卻至較根據步驟(a-2)之溫度低至少10℃之溫度較佳，以至少低30℃更佳，以至少低60℃又更佳。 Suitable precipitation methods are known to those skilled in the art. In the method according to the present invention, it is preferred to cool to a temperature of up to 15 ° C by lowering the volume of the solution obtained in the step (a-2) and/or cooling the solution to carry out the step (b-2'). More preferably at a maximum of 10 ° C, preferably at a maximum of 4 to 8 ° C, and/or by cooling the solution to a temperature of at least 10 ° C lower than the temperature according to step (a-2), preferably It is preferably at least 30 ° C lower, and more preferably at least 60 ° C lower.

於一較佳實施例中，步驟(b-2')係藉由添加介質進行，於該介質中，(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並-[3,4,b]吲哚]-4-胺鹽酸鹽於步驟(a-2)得到之溶液中僅有極低之溶解度(「反溶劑(anti-solvent)」)。該介質以選自由酯類，如乙酸乙酯、乙酸正丙酯、乙酸異丙酯、乙酸正丁酯與乙酸異丁酯；醚類，例如於甲基叔丁基醚、二***與二異丙醚；酮類，例如丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮與己-3-酮；腈類，例如乙腈；啶、乙酸與水組成之群組較佳。 In a preferred embodiment, step (b-2') is carried out by adding a medium in which (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl -4',9'-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano-[3,4,b]indole-4-amine hydrochloride in step (a -2) There is only a very low solubility ("anti-solvent") in the resulting solution. The medium is selected from the group consisting of esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate; ethers such as methyl t-butyl ether, diethyl ether and diiso Propyl ether; ketones such as acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one and hexan-3-one; nitriles such as acetonitrile; pyridine, acetic acid and water The group is preferred.

特佳者為乙酸異丁酯與二***。 Particularly preferred are isobutyl acetate and diethyl ether.

對(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低溶解度之介質、沉澱劑或反溶劑之用量選擇，以可使溶解成分於添加後即開始沉澱較佳。 (1r,4r)-6'-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyridyl The argon [3,4,b]吲哚]-4-amine hydrochloride is selected only in the amount of a medium having a very low solubility, a precipitant or an anti-solvent, so that the dissolved component starts to precipitate immediately after the addition.

亦可將對(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低溶解度之介質之總量分成數個份量，以分成2或3個份量較佳。於此實施例中，溶解成分以於添加最後一份量後開始沉澱較佳。 (1r,4r)-6'-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1 The total amount of '-pyrano[3,4,b]吲哚]-4-amine hydrochloride which has only a very low solubility medium is divided into several parts, preferably divided into 2 or 3 parts. In this embodiment, it is preferred to dissolve the ingredients to initiate precipitation after the last amount is added.

溶解成分之沉澱反應，以添加沉澱劑後立即開始，以添加沉澱劑總量之後較佳，或者延遲2秒至120分鐘之後開始較佳。較佳地，溶解成分之沉澱反應以於最久60分鐘之期間內開始較佳，以最久30分鐘內更佳，以最久20分鐘內又更佳，以最久10分鐘內再更佳，以最久5分鐘內特佳，以最久3分鐘內為首選。 The precipitation reaction of the dissolved components is started immediately after the addition of the precipitating agent, preferably after the total amount of the precipitating agent is added, or after a delay of 2 seconds to 120 minutes. Preferably, the precipitation reaction of the dissolved components starts better during the longest period of 60 minutes, preferably in the longest 30 minutes, preferably in the longest 20 minutes, and preferably in the longest 10 minutes. It is the best in the longest 5 minutes, and the first is 3 minutes.

較佳地，於根據本發明之方法中，步驟(b-2)或(b-2')後之所有步驟係係分別以介於40與0℃之間之溫度進行，以介於35與5℃之間更佳，以介於25與15℃之間又更佳。 Preferably, in the method according to the invention, all the steps after step (b-2) or (b-2') are carried out at a temperature between 40 and 0 ° C, respectively, to More preferably between 5 ° C and even better between 25 and 15 ° C.

較佳地，於根據本發明之方法中，於步驟(b-2')得到之懸浮液係經至少1分鐘之攪拌，以至少2分鐘較佳，以至少3分鐘更佳，以至少5分鐘最佳。 Preferably, in the method according to the present invention, the suspension obtained in the step (b-2') is stirred for at least 1 minute, preferably at least 2 minutes, more preferably at least 3 minutes, and at least 5 minutes. optimal.

較佳地，根據本發明之方法另包括以下步驟：(c-2')分離，以將於步驟(b-2')得到之沉澱物過濾出較佳。 Preferably, the method according to the invention further comprises the step of: (c-2') separating, preferably filtering the precipitate obtained in step (b-2').

較佳地，根據本發明之方法另包括以下步驟：(d-2')將由步驟(c-2')得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (d-2') drying the solid obtained from step (c-2').

於一較佳實施例中，步驟(d-2')係於空氣或惰性氣體氣流中進行，例如氬氣或氮氣氣流。 In a preferred embodiment, step (d-2') is carried out in a stream of air or an inert gas, such as an argon or nitrogen stream.

於另一較佳實施例中，步驟(c-1)係於真空狀態進行，以0至900 mbar之真空狀態更佳，以1至500 mbar之真空狀態又更佳，以10至200 mbar之真空狀態特佳。 In another preferred embodiment, step (c-1) is carried out in a vacuum state, from 0 to 900. The mbar vacuum is better, with a vacuum of 1 to 500 mbar and a vacuum of 10 to 200 mbar.

本發明另一方面涉及利用上述方法獲得之晶形F。 Another aspect of the invention relates to a crystalline form F obtained by the above method.

本發明另一方面涉及晶形G。 Another aspect of the invention relates to Form G.

較佳地，根據本發明之晶形G可具有一個或更多個選自由21.4±0.2(2Θ)、24.5±0.2(2Θ)、25.2±0.2(2Θ)、26.8±0.2(2Θ)、30.5±0.2(2Θ)、31.8±0.2(2Θ)與33.0±0.2(2Θ)等X光繞射波峰組成之群組。於數個較佳實施例中，其晶形包含位於21.4±0.2(2Θ)與26.8±0.2(2Θ)之X光繞射波峰。於數個較佳實施例中，其晶形包含一位於26.8±0.2(2Θ)之X光繞射波峰。 Preferably, the crystal form G according to the present invention may have one or more selected from the group consisting of 21.4 ± 0.2 (2 Θ), 24.5 ± 0.2 (2 Θ), 25.2 ± 0.2 (2 Θ), 26.8 ± 0.2 (2 Θ), 30.5 ± 0.2 (2Θ), a group consisting of 31.8±0.2 (2Θ) and 33.0±0.2 (2Θ) and other X-ray diffraction peaks. In several preferred embodiments, the crystalline form comprises X-ray diffraction peaks at 21.4 ± 0.2 (2 Θ) and 26.8 ± 0.2 (2 Θ). In several preferred embodiments, the crystal form comprises an X-ray diffraction peak at 26.8 ± 0.2 (2 Å).

根據本發明之晶形G之特徵可為其額外具有至少一個選自由13.3±0.2(2Θ)、14.2±0.2(2Θ)、21.8±0.2(2Θ)、28.6±0.2(2Θ)、30.0±0.2(2Θ)與31.3±0.2(2Θ)等X光繞射波峰組成之群組。 The crystal form G according to the present invention may be characterized in that it additionally has at least one selected from the group consisting of 13.3 ± 0.2 (2 Θ), 14.2 ± 0.2 (2 Θ), 21.8 ± 0.2 (2 Θ), 28.6 ± 0.2 (2 Θ), 30.0 ± 0.2 (2 Θ ) A group consisting of X-ray diffraction peaks such as 31.3 ± 0.2 (2 Θ).

此外，根據本發明之晶形G之特徵可為其具有一個或更多個選自由21.4±0.2(2Θ)、24.5±0.2(2Θ)、25.2±0.2(2Θ)、26.8±0.2(2Θ)、30.5±0.2(2Θ)、31.8±0.2(2Θ)與33.0±0.2(2Θ)等X光繞射波峰組成之群組，及選擇性地一個或更多個選自由13.3±0.2(2Θ)、14.2±0.2(2Θ)、21.8±0.2(2Θ)、28.6±0.2(2Θ)、30.0±0.2(2Θ)與31.3±0.2(2Θ)等X光繞射波峰組成之群組，其額外具有至少一個選自由18.6±0.2(2Θ)、26.2±0.2(2Θ)、27.4±0.2(2Θ)、34.2±0.2(2Θ)與34.8±0.2(2Θ)等X光繞射波峰組成之群組。 Further, the crystal form G according to the present invention may be characterized by having one or more selected from the group consisting of 21.4 ± 0.2 (2 Θ), 24.5 ± 0.2 (2 Θ), 25.2 ± 0.2 (2 Θ), 26.8 ± 0.2 (2 Θ), 30.5. Groups of X-ray diffraction peaks such as ±0.2 (2Θ), 31.8±0.2 (2Θ) and 33.0±0.2 (2Θ), and optionally one or more selected from 13.3±0.2(2Θ), 14.2± a group consisting of 0.2 (2 Θ), 21.8 ± 0.2 (2 Θ), 28.6 ± 0.2 (2 Θ), 30.0 ± 0.2 (2 Θ), and 31.3 ± 0.2 (2 Θ), and the like, X-ray diffraction peaks, which additionally have at least one selected from A group consisting of X-ray diffraction peaks such as 18.6 ± 0.2 (2 Θ), 26.2 ± 0.2 (2 Θ), 27.4 ± 0.2 (2 Θ), 34.2 ± 0.2 (2 Θ), and 34.8 ± 0.2 (2 Θ).

所有2Θ值係指利用波長為1.54060 Å之CuKα輻射所測得之X射線繞射圖。 All 2 Θ values refer to X-ray diffraction patterns measured using CuKα radiation at a wavelength of 1.54060 Å.

根據本發明之晶形G之特徵可為其進一步具有一個或更多個選自由274±2 cm-1、642±2 cm-1、1028±2 cm-1、3053±2 cm-1與3077±2 cm-1等拉曼光譜帶組成之群組。 The crystal form G according to the present invention may be further characterized by having one or more selected from the group consisting of 274±2 cm -1 , 642 ± 2 cm -1 , 1028 ± 2 cm -1 , 3053 ± 2 cm -1 and 3077 ± A group consisting of 2 cm -1 and other Raman spectral bands.

根據本發明之晶形G之特徵可為其進一步具有一個或更多個選自由200±2 cm-1、293±2 cm-1、445±2 cm-1、560±2 cm-1、623±2 cm-1、654±2 cm-1、700±2 cm-1、774±2 cm-1、835±2 cm-1、846±2 cm-1、894±2 cm-1、986±2 cm-1、1005±2 cm-1、1070±2 cm-1、1146±2 cm-1、1193±2 cm-1、1242±2 cm-1、1304±2 cm-1、1361±2 cm-1、1422±2 cm-1、1446±2 cm-1、1512±2 cm-1、1582±2 cm-1、1636±2 cm-1、2986±2 cm-1、3006±2 cm-1、3019±2 cm-1、3089±2 cm-1與3164±2 cm-1等拉曼光譜帶組成之群組。 The crystal form G according to the present invention may be further characterized by having one or more selected from the group consisting of: 200±2 cm -1 , 293±2 cm -1 , 445±2 cm -1 , 560±2 cm -1 , 623 ± 2 cm -1 , 654 ± 2 cm -1 , 700 ± 2 cm -1 , 774 ± 2 cm -1 , 835 ± 2 cm -1 , 846 ± 2 cm -1 , 894 ± 2 cm -1 , 986 ± 2 Cm -1 , 1005 ± 2 cm -1 , 1070 ± 2 cm -1 , 1146 ± 2 cm -1 , 1193 ± 2 cm -1 , 1242 ± 2 cm -1 , 1304 ± 2 cm -1 , 1361 ± 2 cm -1 , 1422 ± 2 cm -1 , 1446 ± 2 cm -1 , 1512 ± 2 cm -1 , 1582 ± 2 cm -1 , 1636 ± 2 cm -1 , 2986 ± 2 cm -1 , 3006 ± 2 cm - 1, 3019 ± 2 cm -1, 3089 ± 2 cm -1 and 3164 ± 2 cm -1 Raman spectral bands like the group consisting of.

本發明另一方面涉及一種如上述製備晶形G之方法，其包括以下步驟：(a-2)將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽以一溶媒溶解。 Another aspect of the invention relates to a process for preparing a crystalline form G as described above, which comprises the steps of: (a-2) (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl- 4',9'-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride was dissolved in a solvent.

較佳地，該溶媒係選自由二氯甲烷、N-甲基-2-吡咯啶酮、甲醇、二甲基甲醯胺與其混合物組成之群組。 Preferably, the solvent is selected from the group consisting of dichloromethane, N-methyl-2-pyrrolidone, methanol, dimethylformamide, and mixtures thereof.

於一特佳實施例中，其有機溶媒為二氯甲烷與甲醇之混合物。較佳地，二氯甲烷與甲醇之比例係介於10：1至1：10之範圍之間，以介於7：1至1：5之範圍更佳，以介於6：1至1：3之範圍又更佳，以介於5：1至1：1之範圍再更佳，以介於4：1至2：1之範圍最佳，以介於3.5：1至2.5：1之範圍為首選(體積/體積比)。 In a particularly preferred embodiment, the organic solvent is a mixture of dichloromethane and methanol. Preferably, the ratio of dichloromethane to methanol is between 10:1 and 1:10, more preferably in the range of 7:1 to 1:5, and is between 6:1 and 1: The range of 3 is better, with a range of 5:1 to 1:1, preferably between 4:1 and 2:1, ranging from 3.5:1 to 2.5:1. Preferred (volume/volume ratio).

較佳地，於根據本發明之方法中，步驟(a-2)係於相應溶媒之沸點或較低之溫度中進行，以不高於80℃之溫度較佳，以不高於60℃更佳，以不高於40℃又更佳，以20至40℃之溫度範圍為首選。 Preferably, in the method according to the present invention, the step (a-2) is carried out at a boiling point or a lower temperature of the corresponding solvent, preferably at a temperature not higher than 80 ° C, and more preferably not higher than 60 ° C. Preferably, it is preferably not higher than 40 ° C, and the temperature range of 20 to 40 ° C is preferred.

較佳地，其方法另包括以下步驟：(b-2')將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽從於步驟(a-2)得到之溶液中沉澱出。 Preferably, the method further comprises the step of: (b-2')-(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydrogen -3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride precipitated from the solution obtained in step (a-2) .

適用之沉澱方法已為熟知此技術領域者所知。於根據本發明之方法中，可藉由降低由步驟(a-2)得到之溶液之體積及/或將該溶液冷卻進行步驟(b-2')，以冷卻至最高15℃之溫度較佳，以最高10℃更佳，以最高4至8℃最佳，及/或藉由將該溶液冷卻，以冷卻至較根據步驟(a-2)之溫度低至少10℃之溫度較佳，以至少低30℃更佳，以至少低60℃又更佳。 Suitable precipitation methods are known to those skilled in the art. In the method according to the present invention, it is preferred to cool to a temperature of up to 15 ° C by lowering the volume of the solution obtained in the step (a-2) and/or cooling the solution to carry out the step (b-2'). More preferably at a maximum of 10 ° C, preferably at a maximum of 4 to 8 ° C, and/or by cooling the solution to a temperature of at least 10 ° C lower than the temperature according to step (a-2), preferably It is preferably at least 30 ° C lower, and more preferably at least 60 ° C lower.

於一較佳實施例中，步驟(b-2')係藉由添加介質進行，於該介質中，(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並-[3,4,b]吲哚]-4-胺鹽酸鹽於步驟(a-2)得到之溶液中僅有極低之溶解度(「反溶劑(anti-solvent)」)。 In a preferred embodiment, step (b-2') is carried out by adding a medium in which (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl -4',9'-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano-[3,4,b]indole-4-amine hydrochloride in step (a -2) There is only a very low solubility ("anti-solvent") in the resulting solution.

較佳地，該介質為啶。 Preferably, the medium is a pyridine.

對(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低溶解度之介質、沉澱劑或反溶劑之用量選擇，以可使溶解成分於添加後2天內開始沉澱較佳，以1天內更佳。 (1r,4r)-6'-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyridyl Methyl [3,4,b]吲哚]-4-amine hydrochloride is selected only in the form of a very low solubility medium, precipitant or anti-solvent, so that the dissolved components can be precipitated within 2 days after the addition. Good, better in 1 day.

亦可將對(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽僅有極低溶解度之介質之總量分成數個份量，以分成2或3個份量較佳。於此實施例中，溶解成分以於添加最後一份量後開始沉澱較佳。 (1r,4r)-6'-Fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1 The total amount of '-pyrano[3,4,b]吲哚]-4-amine hydrochloride which has only a very low solubility medium is divided into several parts, preferably divided into 2 or 3 parts. In this embodiment, it is preferred to dissolve the ingredients to initiate precipitation after the last amount is added.

較佳地，於根據本發明之方法中，步驟(b-2)或(b-2')後之所有步驟係係分別以介於40與0℃之間之溫度進行，以介於35與5℃之間更佳，以介於25與15℃之間又更佳。 Preferably, in the method according to the invention, all the steps after step (b-2) or (b-2') are carried out at a temperature between 40 and 0 ° C, respectively, to More preferably between 5 ° C and even better between 25 and 15 ° C.

較佳地，根據本發明之方法另包括以下步驟：(c-2')分離，以將於步驟(b-2')得到之沉澱物過濾出較佳。 Preferably, the method according to the invention further comprises the step of: (c-2') separating, preferably filtering the precipitate obtained in step (b-2').

較佳地，根據本發明之方法另包括以下步驟：(d-2')將由步驟(c-2')得到之固體乾燥。 Preferably, the method according to the invention further comprises the step of: (d-2') drying the solid obtained from step (c-2').

較佳地，於根據本發明之方法中，步驟(d-2')係於空氣或惰性氣體氣流中進行，例如氬氣或氮氣氣流。 Preferably, in the process according to the invention, step (d-2') is carried out in a stream of air or an inert gas, such as an argon or nitrogen stream.

本發明另一方面涉及利用上述方法獲得之晶形G。 Another aspect of the invention relates to a crystalline form G obtained by the above method.

於數個實施例中，可由本發明之固體形式獲得高產率及高純度之鹽酸鹽形式之(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺。這些形式之進一步區別在於其具有實質上不同之性質，該性質可能具有優勢。 In several embodiments, (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4 in the form of the hydrochloride salt of high yield and high purity can be obtained from the solid form of the present invention. ',9'-Dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indole]-4-amine. A further difference between these forms is that they have substantially different properties that may have advantages.

於數個較實施例中，本發明之固體形式之特徵為更容易處理及更精準(甚至確切精準)之活性成分量測。 In a number of comparative examples, the solid form of the invention is characterized by easier handling and more precise (even exact) active ingredient measurements.

於數個實施例中，意外地發現(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽可形成四種非溶劑化物形式(晶形A、B、D與F)、一種水合物(晶形C)及兩種含有不同有機溶媒之溶劑化物(晶形E與G)。 In several examples, (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[ring] was unexpectedly discovered. Hexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride can form four unsolvated forms (forms A, B, D and F), a hydrate (Form C) and two solvates containing different organic solvents (Forms E and G).

於數個實施例中，意外地發現可利用平衡時間較短之結晶技術獲得晶形A、D與E或其混合物。於數個實施例中，意外地發現利用這些快速結晶技術所獲得之主要形式為晶形A。 In several embodiments, it has been unexpectedly discovered that crystalline forms A, D and E or mixtures thereof can be obtained using a crystallization technique with a relatively short equilibrium time. In several embodiments, it has surprisingly been found that the predominant form obtained using these rapid crystallization techniques is Form A.

於數個實施例中發現晶形A不具吸濕性。於數個實施例中發現可藉由將晶形C乾燥而獲得晶形A。 Form A was found to be non-hygroscopic in several examples. It has been found in several embodiments that Form A can be obtained by drying Form C.

於數個實施例中，發現可利用較緩慢之結晶技術，例如懸浮平衡，獲得晶形B。於數個實施例中，意外地發現可利用此類較緩慢之結晶技術將晶形A、B、C、D與F轉化為晶形B。於數個實施例中，發現晶形B於室溫之熱力穩定性最高。 In several embodiments, it has been found that Form B can be obtained using slower crystallization techniques, such as suspension equilibration. In several embodiments, it has been unexpectedly discovered that crystalline forms A, B, C, D, and F can be converted to Form B using such slower crystallization techniques. In several examples, Form B was found to have the highest thermal stability at room temperature.

本發明之範疇亦包括晶形A、B、C、D、E、F與G之混合物，以兩種或三種此晶形之混合物較佳。 Also included within the scope of the invention are mixtures of crystalline forms A, B, C, D, E, F and G, preferably in mixtures of two or three such crystalline forms.

例如，可藉由去除一部份水合物之水分，由晶形C獲得晶形A與C之混合物，或可藉由部分地懸浮平衡，由含有晶形A之懸浮液獲 得晶形A與B之混合物。 For example, a mixture of Forms A and C can be obtained from Form C by removing moisture from a portion of the hydrate, or can be obtained from a suspension containing Form A by partial suspension equilibrium. A mixture of crystal forms A and B is obtained.

於一較佳實施例中，可隨即將根據本發明之晶形轉化為非晶形。 In a preferred embodiment, the crystalline form according to the present invention can then be converted to an amorphous form.

本發明另一方面涉及一種固體形式，尤其是本文所描述用於治療疼痛之晶形及/或非晶形。 Another aspect of the invention relates to a solid form, especially a crystalline form and/or an amorphous form for treating pain as described herein.

本發明另一方面涉及治療疼痛之方法，其包含對有其需求之患者(例如，被診斷出罹患疼痛疾患之患者)施用一如本文所述之固體形式。 Another aspect of the invention relates to a method of treating pain comprising administering a solid form as described herein to a patient in need thereof (e.g., a patient diagnosed with a painful condition).

本發明另一方面涉及治療疼痛之方法，其包含對有需求之患者(例如，被診斷出罹患疼痛疾患之患者)施用一種含有如本文所述之固體形式之醫藥組成物。 Another aspect of the invention relates to a method of treating pain comprising administering to a patient in need thereof (e.g., a patient diagnosed with a pain disorder) a pharmaceutical composition comprising a solid form as described herein.

疼痛一詞於本文以包括但不限於選自由發炎引起之疼痛、術後疼痛、神經性疼痛、糖尿病性神經痛、急性疼痛、慢性疼痛、內臟疼痛、偏頭痛與癌症疼痛構成之群組較佳。 The term pain is preferably included herein, including but not limited to, selected from the group consisting of pain caused by inflammation, postoperative pain, neuropathic pain, diabetic neuropathic pain, acute pain, chronic pain, visceral pain, migraine and cancer pain. .

於數個較佳實施例中，其固體形式，尤其係根據本發明之晶形及/或非晶形，係用於治療急性、內臟、神經性或慢性疼痛(參見WO 2008/040481)。 In several preferred embodiments, the solid form, especially in accordance with the crystalline form and/or amorphous form of the invention, is used to treat acute, visceral, neurological or chronic pain (see WO 2008/040481).

本發明另一方面涉及一種含有固體形式之醫藥組成物，特別係如本文描述之晶形及/或非晶形，及選擇性地一種或更多種如下述合適之添加物及/或佐劑。 Another aspect of the invention relates to a pharmaceutical composition comprising a solid form, in particular a crystalline form and/or an amorphous form as described herein, and optionally one or more suitable additives and/or adjuvants as described below.

於數個較佳實施例中，其醫藥組成物包含介於約0.001%以重量計至40%以重量計之一種或多種固體形式，特別係如本文描述之晶形及/或非晶形。於數個較佳實施例中，其醫藥組成物包含介於約0.001%以重量計至20%以重量計之間之一種或多種固體形式，特別係如本文描述之晶形及/或非晶形。於數個較佳實施例中，其醫藥組成物包含介於約0.001%以重量計至10%以重量計之間之一種或多種固體形式，特別係如本文描述之晶形及/或非晶形。於數個較佳實施例中，其醫藥組成物包含介於約0.001%以重量計至 5%以重量計之間之一種或多種固體形式，特別係如本文描述之晶形及/或非晶形。於數個較佳實施例中，該醫藥組成物包含介於約0.001%以重量計至1%以重量計之間之一種或多種固體形式，特別係如本文描述之晶形及/或非晶形。於數個較佳實施例中，該醫藥組成物包含介於約0.01%以重量計至1%以重量計之間之一種或多種固體形式，特別係如本文描述之晶形及/或非晶形。 In several preferred embodiments, the pharmaceutical composition comprises from about 0.001% by weight to 40% by weight of one or more solid forms, particularly crystalline and/or amorphous as described herein. In several preferred embodiments, the pharmaceutical composition comprises between about 0.001% by weight and 20% by weight of one or more solid forms, particularly crystalline and/or amorphous as described herein. In several preferred embodiments, the pharmaceutical composition comprises between about 0.001% by weight and 10% by weight of one or more solid forms, particularly crystalline and/or amorphous as described herein. In several preferred embodiments, the pharmaceutical composition comprises between about 0.001% by weight to 5% by weight of one or more solid forms, especially crystalline and/or amorphous as described herein. In several preferred embodiments, the pharmaceutical composition comprises between about 0.001% by weight and 1% by weight of one or more solid forms, particularly crystalline and/or amorphous as described herein. In several preferred embodiments, the pharmaceutical composition comprises between about 0.01% by weight to 1% by weight of one or more solid forms, particularly crystalline and/or amorphous as described herein.

適合用於判定(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺之鹽酸鹽含量之方法已為熟知此技術領域者所知，例如X光粉末繞射、元素分析、拉曼光譜、紅外線光譜、色層分析、核磁共振光譜、熱分析、電泳、原子吸收光譜、能量放射X射線光譜等分析方法，其中包括例如，示差掃描熱量分析、熱重分析法、溫度調幅式示差掃描熱卡計、高速示差掃描熱卡計、熔點、熱臺X光粉末繞射、溫載台顯微鏡、鎔解熱、微區熱分析、熱量測定法、微熱量測定法。 Suitable for the determination of (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1 Methods for the hydrochloride content of '-pyrano[3,4,b]吲哚]-4-amine are known to those skilled in the art, such as X-ray powder diffraction, elemental analysis, Raman spectroscopy, Infrared spectroscopy, chromatography, nuclear magnetic resonance spectroscopy, thermal analysis, electrophoresis, atomic absorption spectroscopy, energy emission X-ray spectroscopy and other analytical methods, including, for example, differential scanning calorimetry, thermogravimetric analysis, temperature-modulated differential scanning calorie Meter, high-speed differential scanning calorimeter, melting point, hot stage X-ray powder diffraction, temperature stage microscope, enthalpy heat, micro-zone thermal analysis, calorimetry, microcalorimetry.

較佳地，該醫藥組合物可用於治療疼痛。 Preferably, the pharmaceutical composition is useful for treating pain.

本發明又另一方面涉及含有一種固體形式之藥劑，特別係如本文描述之晶形及/或非晶形。於一較佳實施例中，其藥劑為固體藥劑形式。該藥劑以製備為口服投藥之形式較佳。然而，亦可製備為其它形式，例如口腔含化、舌下、經黏膜、直腸、腰內(intralumbal)、腹膜內、經皮、靜脈內、肌內、臀肌內、皮內及皮下等給藥方式。 Yet another aspect of the invention relates to a medicament comprising a solid form, in particular a crystalline form and/or an amorphous form as described herein. In a preferred embodiment, the medicament is in the form of a solid pharmaceutical. The agent is preferably prepared in the form of an oral administration. However, it can also be prepared in other forms, such as buccal, sublingual, transmucosal, rectal, intralumbal, intraperitoneal, transdermal, intravenous, intramuscular, intragluteal, intradermal, and subcutaneous. Medication.

取決於其結構，該藥劑(劑量形式)以含有合適之添加物及/或佐劑較佳。就本發明之意義而言，合適之添加物及/或佐劑係熟知此技術領域者所知、可用於形成蓋倫配方之任何物質。所使用之佐劑及劑量之選擇取決於投藥方式，即口服、靜脈內、腹膜內、皮內、肌內、鼻內、口腔含化或局部等投藥方式。 Depending on its structure, the agent (dosage form) is preferably contained with suitable additives and/or adjuvants. Suitable additives and/or adjuvants are known in the sense of the present invention to be any material known to those skilled in the art that can be used to form a galenic formulation. The choice of adjuvant and dosage to be used depends on the mode of administration, ie, oral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal or topical administration.

於數個較佳實施例中，其劑型含有40±35 μg之一種或多種 本文描述之晶形，以40±30 μg更佳，以40±25 μg又更佳，以40±20 μg再更佳，以40±15 μg又再更佳，以40±10 μg最佳，以40±5 μg特佳。於數個較佳實施例中，其劑型含有400±375 μg或400±350 μg之一種或多種本文描述之晶形，以400±300 μg更佳，以400±250 μg又更佳，以400±200 μg再更佳，以400±150 μg又再更佳，以40±100 μg最佳，以400±50 μg特佳。 In several preferred embodiments, the dosage form contains one or more of 40 ± 35 μg The crystal form described herein is preferably 40±30 μg, more preferably 40±25 μg, even more preferably 40±20 μg, even more preferably 40±15 μg, and optimally 40±10 μg. 40±5 μg is especially good. In several preferred embodiments, the dosage form contains one or more of the crystal forms described herein, 400 ± 375 μg or 400 ± 350 μg, more preferably 400 ± 300 μg, more preferably 400 ± 250 μg, and 400 ± ± 200 μg is even better, and 400 ± 150 μg is even better, preferably 40 ± 100 μg, and 400 ± 50 μg.

適合口服投藥之製劑為片劑、嚼錠劑、錠劑、膠囊劑、顆粒劑、滴劑、液體或糖漿等形式；適合非口服、局部及吸入性投藥之製劑為溶液、懸浮液、容易復水之乾燥製劑與噴霧劑。另一可能之製劑為直腸投藥之栓劑。合適之經皮應用形式之實例為溶解形式、貼劑或硬高劑等藥性持久之應用，其可能添加促進皮膚滲透之藥劑。 The preparations suitable for oral administration are in the form of tablets, chewable tablets, troches, capsules, granules, drops, liquids or syrups; preparations suitable for non-oral, topical and inhalation administration are solutions, suspensions, and easy to reconstitute Dry preparation of water and spray. Another possible preparation is a suppository for rectal administration. Examples of suitable transdermal application forms are pharmaceutically persistent applications such as dissolution forms, patches or hardening agents, which may add agents which promote skin penetration.

口服劑型之佐劑與添加劑之實例為分解劑、潤滑劑、黏合劑、充填劑、脫模劑，其可為溶媒、調味劑、糖，尤其係載體、稀釋劑、著色劑、抗氧化物等。 Examples of adjuvants and additives for oral dosage forms are decomposers, lubricants, binders, fillers, and release agents, which may be solvents, flavoring agents, sugars, especially carriers, diluents, colorants, antioxidants, etc. .

包括蠟或脂肪酸酯在內之其它物質可用於栓劑及載體物質、防腐劑、懸浮助劑等，可應用於腸外投藥形式。 Other substances including waxes or fatty acid esters can be used for suppositories and carrier materials, preservatives, suspension aids, etc., and can be applied to parenteral administration forms.

佐劑可係，例如：水、乙醇、2-丙醇、甘油、乙烯二醇、丙二醇、聚乙烯二醇、聚丙烯乙二醇、葡萄糖、果糖、乳糖、蔗糖、右旋糖、廢糖蜜、澱粉、改質澱粉、明膠、山梨醇、肌醇、甘露醇、微晶纖維素、甲基纖維素、羧甲基纖維素、乙酸纖維素、蟲膠、鯨蠟醇、聚乙烯吡咯啶酮、石蠟、蠟、天然與合成橡膠、***膠、海藻酸、葡聚糖、飽和及未飽和脂肪酸、硬脂酸、硬脂酸鎂、硬脂酸鋅、硬脂酸甘油酯、十二烷基硫酸鈉、食用油、芝麻油、椰子油、花生油、大豆油、卵磷脂、乳酸鈉、聚氧乙烯與丙烯脂肪酸酯、山梨糖醇酐脂肪酸酯、山梨酸、苯甲酸、檸檬酸、 抗壞血酸、單寧酸、氯化鈉、氯化鉀、氯化鎂、氯化鈣、氧化鎂、氧化鋅、二氧化矽、氧化鈦、二氧化鈦、硫酸鎂、硫酸鋅、硫酸鈣、鉀鹼、磷酸鈣、磷酸二鈣、溴化鉀、碘化鉀、滑石、高嶺土、果膠、聚乙烯吡咯烷酮維酮(crospovidon)、洋菜與皂土。 The adjuvant may be, for example, water, ethanol, 2-propanol, glycerin, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, waste molasses, Starch, modified starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, Paraffin, wax, natural and synthetic rubber, gum arabic, alginic acid, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, lauryl sulfate Sodium, edible oil, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and propylene fatty acid esters, sorbitan fatty acid esters, sorbic acid, benzoic acid, citric acid, Ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, cerium oxide, titanium oxide, titanium dioxide, magnesium sulfate, zinc sulfate, calcium sulfate, potash, calcium phosphate, Dicalcium phosphate, potassium bromide, potassium iodide, talc, kaolin, pectin, crospovidon, amaranth and bentonite.

此類藥劑與醫藥組成物係利用熟知製藥技術領域者所熟知之方式、儀器、方法及程序製備而成，例如「雷明頓之藥物科學」(“Remington’s Pharmaceutical Sciences”)，A.R.Gennaro(編輯)，第17版，麥克出版公司(Mack Publishing Company)，Easton，Pa.(1985)之描述，特別係第8部第76至第93章。 Such pharmaceutical and pharmaceutical compositions are prepared by methods, apparatus, methods and procedures well known to those skilled in the art of pharmaceutical technology, such as "Remington's Pharmaceutical Sciences", ARGennaro (ed.), The 17th edition, described by Mack Publishing Company, Easton, Pa. (1985), in particular Part 8 of Chapters 76-93.

因此，例如於片劑之固體配方中，可將該藥劑之活性物質與醫藥載體物質一起製成顆粒，例如含有玉米澱粉、乳糖、蔗糖、山梨醇、滑石、硬脂酸鎂、磷酸二鈣或藥理可接受之橡膠等成分之傳統片劑成分，及例如水之藥物稀釋劑，以使其形成含有均勻分散之活性物質之固體合成物。均勻分散於此解讀為該活性物質係均勻地分散於該合成物中，使其便於分成完全等效之標準劑型，例如片劑、膠囊及錠劑。隨後可將該固體合成物分成標準劑型。亦可將該片劑或丸劑塗覆或複合，以製備緩釋劑型。合適之塗覆劑包括聚合酸及聚合酸與蟲膠、鯨蠟醇及/或醋酸纖維等物質之混合物。 Thus, for example, in a solid formulation of a tablet, the active substance of the agent may be granulated with a pharmaceutical carrier material, for example, containing corn starch, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or A conventional tablet component of a pharmaceutically acceptable rubber or the like, and a pharmaceutical diluent such as water, to form a solid composition containing a uniformly dispersed active material. Uniform Dispersion Here, it is interpreted that the active material is uniformly dispersed in the composition to facilitate its separation into fully equivalent standard dosage forms such as tablets, capsules and lozenges. This solid composition can then be separated into standard dosage forms. The tablets or pills may also be coated or compounded to prepare a sustained release dosage form. Suitable coating agents include mixtures of polymeric acids and polymeric acids with materials such as shellac, cetyl alcohol and/or acetate.

於一本發明固體形式之實施例中，尤其是如本文描述之晶形及/或非晶形，係存在於立即釋放形式。 In an embodiment of the solid form of the invention, especially crystalline and/or amorphous as described herein, is present in an immediate release form.

於另一本發明固體形式之實施例中，尤其是如本文描述之晶形及/或非晶形，係至少部分地以控制釋放之形式存在。尤其，該活性成分可由可經口服、直腸或經皮應用之製劑中緩慢地釋放出。 In another embodiment of the solid form of the invention, especially crystalline and/or amorphous as described herein, is present at least partially in controlled release form. In particular, the active ingredient can be slowly released from preparations which can be administered orally, rectally or transdermally.

該藥劑以製備成每日服用一次、每日兩次(bid)或每日三次較佳，以每日一次或每日兩次較佳。 The medicament is preferably administered once daily, twice daily (bid) or three times daily, preferably once daily or twice daily.

控制釋放一詞於本文係指除了立即釋放劑型以外之所有釋放形式，例如延緩釋放、持續釋放、緩慢釋放、延長釋放及類似之釋放形式。用於獲得此類釋放形式之術語及方式、儀器、方法及程序為任何熟知此技術領域者所知。 The term controlled release is used herein to mean all forms of release other than immediate release dosage forms, such as delayed release, sustained release, slow release, extended release, and the like. The terms and means, instruments, methods and procedures for obtaining such release forms are known to those skilled in the art.

於本發明之另一實施例中，˙該藥劑係製備成可供口服投藥；及/或˙該藥劑為固體及/或壓縮及/或薄膜塗層之藥劑形式；及/或˙該藥劑可將該固體形式緩慢地由基質釋放出，尤其是如本文描述之晶形及/或非晶形；及/或˙該藥劑所含之該固體形式，尤其是如本文描述之晶形及/或非晶形，其以該藥劑總重量計之含量為0.001至99.999%以重量計，以0.1至99.9%以重量計更佳，以1.0至99.0%以重量計又更佳，以2.5至80%以重量計再更佳，以5.0至50%以重量計最佳，以7.5至40%以重量計特佳；及/或˙該藥劑含有一種藥理上相容之載體及/或藥理上相容之佐劑；及/或˙該藥劑之總質量係介於25至2000 mg之間，以50至1800 mg更佳，以60至1600 mg又更佳，以70至1400 mg再更佳，以80至1200 mg最佳，以100至1000 mg特佳；及/或˙該藥劑係選自由片劑、膠囊、丸劑與顆粒組成之群組。 In another embodiment of the invention, the medicament is prepared for oral administration; and/or the medicament is in the form of a solid and/or compressed and/or film coated medicament; and/or The solid form is slowly released from the substrate, especially crystalline and/or amorphous as described herein; and/or 固体 the solid form contained in the agent, especially crystalline and/or amorphous as described herein, It is preferably 0.001 to 99.999% by weight, more preferably 0.1 to 99.9% by weight, more preferably 1.0 to 99.0% by weight, and further preferably 2.5 to 80% by weight, based on the total weight of the pharmaceutical agent. More preferably, it is preferably 5.0 to 50% by weight, particularly preferably 7.5 to 40% by weight; and/or ̇ the agent contains a pharmaceutically compatible carrier and/or a pharmacologically compatible adjuvant; And/or ̇ the total mass of the agent is between 25 and 2000 mg, more preferably from 50 to 1800 mg, more preferably from 60 to 1600 mg, even more preferably from 70 to 1400 mg, and from 80 to 1200 mg. Most preferably, it is preferably from 100 to 1000 mg; and/or ̇ the agent is selected from the group consisting of tablets, capsules, pills and granules.

該藥劑可製備為單純片劑及塗層片劑(例如薄膜塗層或錠劑)之形式。該片劑通常係圓形與雙凸形，但亦可係長橢圓形。亦可係包含在囊劑(sachet)或膠囊中，或壓縮成崩解片之顆粒、球形、丸劑或為膠囊之形式。 The medicament may be prepared in the form of a simple tablet and a coated tablet such as a film coating or lozenge. The tablets are generally round and biconvex, but may also be oblong. It may also be in the form of a sachet or capsule, or compressed into a disintegrating tablet in the form of granules, spheres, pills or capsules.

本發明又另一方面涉及固體形式之用途，尤其是使用如本文 描述之晶形及/或非晶形製備藥劑。該藥劑以適用於治療疼痛較佳。 Yet another aspect of the invention relates to the use of a solid form, especially as herein The crystalline form and/or amorphous form of the preparation agent is described. The agent is preferably suitable for treating pain.

本發明又另一方面涉及使用該固體形式治療疼痛，尤其是以如本文描述之晶形及/或非晶形。 Yet another aspect of the invention relates to the use of the solid form for the treatment of pain, particularly in crystalline form and/or amorphous form as described herein.

此外，本發明涉及一種治療患者之疼痛之方法，治療對象以哺乳動物較佳，其包括對患者施用有效劑量之固體形式，特別是如本文描述之晶形及/或非晶形。 Furthermore, the invention relates to a method of treating pain in a patient, preferably in a mammal, comprising administering to the patient an effective amount of a solid form, in particular a crystalline form and/or an amorphous form as described herein.

第1a圖至第1g圖顯示晶形A、B、C、D、E、F與G之粉末X光繞射型態。 Figures 1a through 1g show powder X-ray diffraction patterns of Forms A, B, C, D, E, F and G.

第2a圖至第2g圖顯示晶形A、B、C、D、E、F與G之拉曼光譜。 Figures 2a to 2g show Raman spectra of crystal forms A, B, C, D, E, F and G.

下列實例之目的為更詳細地說明本發明，但不可解釋為其範圍限制。 The following examples are intended to illustrate the invention in more detail, but are not to be construed as limiting its scope.

實施例中使用了下列縮寫： The following abbreviations are used in the examples:

除非另有明確規範，所有溶媒混合物皆為體積/體積比。 All solvent mixtures are volume/volume ratios unless otherwise specifically stated.

(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺之合成方法 (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyran And [3,4,b]吲哚]-4-amine synthesis method

於0℃，將(4-(二甲胺基)-4-苯基環己酮(3 g，13.82 mmol)、2-(5-氟-1H-吲哚-3-基)乙醇(2.47 g，13.82 mmol)及150 mL之二氯甲烷置放於一燒瓶中。迅速地添加一溶於3 mL之二氯甲烷之三氟甲磺酸三甲基矽酯(3 mL，15.5 mmol)溶液。該反應混合物之顏色轉換為紫色，且溫度升高至10℃。將該反應混合物於冰浴中冷卻並攪拌20分鐘。同時可發現固體沉澱出。移除冰浴槽並將該反應混合物攪拌於室溫3至3.5小時。隨後添加50 mL之氫氧化鈉(1N)，並 將該反應混合物再攪拌10分鐘。其顏色轉換成黃色且有固體沉澱出。為完成沉澱反應，將該反應混合物(兩個液相)再攪拌20分鐘，同時將其於冰浴冷卻。最後，將該固體過濾出。隨後以800 mL之2-丙醇將所得之固體(4.2 g)再結晶。 (4-(Dimethylamino)-4-phenylcyclohexanone (3 g, 13.82 mmol), 2-(5-fluoro-1H-indol-3-yl)ethanol (2.47 g) at 0 °C 13.82 mmol) and 150 mL of methylene chloride were placed in a flask, and a solution of trimethylsulfonate triflate (3 mL, 15.5 mmol) dissolved in 3 mL of dichloromethane was quickly added. The color of the reaction mixture was converted to purple, and the temperature was raised to 10 C. The reaction mixture was cooled in an ice bath and stirred for 20 minutes while solids were found to precipitate. The ice bath was removed and the reaction mixture was stirred in the chamber. Warm for 3 to 3.5 hours, then add 50 mL of sodium hydroxide (1N) and The reaction mixture was stirred for a further 10 minutes. Its color is converted to yellow and a solid precipitates out. To complete the precipitation reaction, the reaction mixture (two liquid phases) was stirred for a further 20 minutes while it was cooled in an ice bath. Finally, the solid was filtered off. The resulting solid (4.2 g) was then recrystallized from 800 mL of 2-propanol.

產率：3.5 g。 Yield: 3.5 g.

為提升產率，將液態濾液(水及二氯甲烷)分離。將水溶液以20 mL之二氯甲烷萃取3次。將有機相合併並以硫酸鎂乾燥，隨後將溶媒去除直至乾燥。隨後將所得之固體(1.7 g)於800 mL之2-丙醇回流中再結晶。 To increase the yield, the liquid filtrate (water and dichloromethane) was separated. The aqueous solution was extracted 3 times with 20 mL of dichloromethane. The organic phases were combined and dried over magnesium sulfate, then the solvent was removed and dried. The resulting solid (1.7 g) was then recrystallized from 800 mL of 2-propanol reflux.

A)晶形A之合成方法 A) Synthesis method of crystal form A

將303 mg之(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺以50 mL之丙酮及2 mL之四氫呋喃溶解。添加1.6 mL之氫氯酸(0.5 M於水中)。於攪拌一小段時間後將鹽沉澱出。將所得之懸浮液於室溫攪拌1天。將所得之固體沉澱出並於空氣中乾燥。以核磁共振、粉末X光繞射、傳立葉轉換拉曼光譜、熱重-傅立葉轉換紅外線連用光譜、示差掃描熱量分析、元素分析及動態濕氣吸附分析檢測晶形A之固體形式特徵(參照「分析」段落)。 303 mg of (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1 '-Pyrando[3,4,b]indole-4-amine was dissolved in 50 mL of acetone and 2 mL of tetrahydrofuran. Add 1.6 mL of hydrochloric acid (0.5 M in water). The salt was precipitated after stirring for a short period of time. The resulting suspension was stirred at room temperature for 1 day. The resulting solid was precipitated and dried in air. NMR, powder X-ray diffraction, transfer-leaf conversion Raman spectroscopy, thermogravimetry-Fourier transform infrared spectroscopy, differential scanning calorimetry, elemental analysis and dynamic moisture adsorption analysis to detect the solid form characteristics of Form A (see "Analysis" "paragraph).

B)晶形B之合成方法 B) Synthesis method of crystal form B

將3.07 g之(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺懸浮於520 mL之丙酮/四氫呋喃(25：1，體積/體積比)中。僅有小量之固體存留。緩慢地添加18 mL之氫氯酸(0.5 M於水中)，可發現有更多沉澱物形成。將該懸浮液於室溫攪拌5天。將所得之固體過濾出，並於真空狀態乾 燥1.5小時。以核磁共振、粉末X光繞射、傳立葉轉換拉曼光譜、熱重-傅立葉轉換紅外線連用光譜、示差掃描熱量分析、元素分析及動態濕氣吸附分析等方法檢測所得之晶形B之晶質固體(2.35 g，70%)特徵(參照「分析」段落)。 3.07 g of (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1 The --pyrano[3,4,b]indole-4-amine was suspended in 520 mL of acetone/tetrahydrofuran (25:1, volume/volume ratio). Only a small amount of solids remain. Slowly adding 18 mL of hydrochloric acid (0.5 M in water) revealed more precipitate formation. The suspension was stirred at room temperature for 5 days. The resulting solid is filtered off and dried under vacuum Dry for 1.5 hours. The crystal solids of Form B obtained by NMR, powder X-ray diffraction, Fourier transform Raman spectroscopy, thermogravimetry-Fourier transform infrared spectroscopy, differential scanning calorimetry, elemental analysis and dynamic moisture adsorption analysis (2.35 g, 70%) features (refer to the "Analysis" section).

高效能液相層析分析顯示該化合物之純度>99.9%。通常存在於該自由鹼之高效能液相層析分光譜之雜質峰於此樣本係低於檢測極限。因此，將自由鹼轉化為氫氯酸加成鹽，及隨後將所得之氫氯酸鹽晶化，可顯著地純化該化合物。 High performance liquid chromatography analysis showed the purity of the compound to be >99.9%. The impurity peaks normally present in the high performance liquid chromatography of the free base are below the detection limit for this sample. Thus, the conversion of the free base to the hydrochloric acid addition salt and subsequent crystallization of the resulting hydrochloride salt can significantly purify the compound.

實例1 Example 1

酸鹼反應實驗 Acid-base reaction experiment

於室溫，將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺(於自由鹼之形式)溶解或懸浮於不同溶媒中。若所得之溶液呈混濁狀態，可將該溶液過濾。隨後於該溶液中添加氫氯酸。將所得之懸浮液於室溫攪拌不同時間長度。將所得之固體過濾出，以不同條件乾燥(真空狀態，氮氣氣流或不同之相對濕度)，並以粉末X光繞射及/或傳立葉轉換拉曼光譜檢測其特徵。 (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1, at room temperature 1'-Pyrando[3,4,b]indole-4-amine (in the form of a free base) is dissolved or suspended in a different solvent. If the resulting solution is cloudy, the solution can be filtered. Hydrochloric acid is then added to the solution. The resulting suspension was stirred at room temperature for different lengths of time. The resulting solid was filtered off, dried under different conditions (vacuum state, nitrogen gas stream or different relative humidity), and characterized by powder X-ray diffraction and/or Fourier transform Raman spectroscopy.

實驗條件與結果之細節總結於下表。所得形式之特徵細節參見「分析」段落。 The experimental conditions and details of the results are summarized in the table below. See the "Analysis" section for details on the features of the resulting form.

由上方表格中顯見於懸浮平衡時間較長之實驗所獲得之主要形式為B，而A、D與E出現於懸浮平衡時間較短之實驗中。C形式可能為水合物，且僅見於含大量水之實驗中。其於乾燥後轉化為晶形A。實驗中未發現非晶形。 The main form obtained from the experiments in the above table, which is apparent in the suspension equilibrium time is longer, and A, D and E appear in the experiment with shorter suspension equilibrium time. The C form may be a hydrate and is only found in experiments containing large amounts of water. It is converted to Form A after drying. No amorphous form was found in the experiment.

實例2 Example 2

快速沉澱實驗 Rapid precipitation experiment

三種儲備原液之製備方式如下： The three stock solutions are prepared as follows:

儲備原液a：將110 mg之晶形B懸浮於40 mL之N-甲基-2-吡咯啶酮中。將該懸浮液攪拌2小時。以過濾之方式去除殘餘之小量沉澱劑。 Stock stock a: 110 mg of Form B was suspended in 40 mL of N-methyl-2-pyrrolidone. The suspension was stirred for 2 hours. The residual small amount of precipitant is removed by filtration.

儲備原液b：將254 mg之晶形B懸浮於40 mL之二氯甲烷/甲醇3：1(體積/體積)中。將該懸浮液攪拌1天。以過濾之方式去除殘餘之小量沉澱劑。 Stock stock b: 254 mg of Form B was suspended in 40 mL of dichloromethane/methanol 3:1 (vol/vol). The suspension was stirred for 1 day. The residual small amount of precipitant is removed by filtration.

儲備原液c：將246 mg之晶形B懸浮於40 mL之二氯甲烷/甲醇3：1(體積/體積)中。將該懸浮液攪拌3天。以過濾之方式去除殘餘之小量沉澱劑。 Stock stock solution c: 246 mg of Form B was suspended in 40 mL of dichloromethane/methanol 3:1 (vol/vol). The suspension was stirred for 3 days. The residual small amount of precipitant is removed by filtration.

於各個沉澱實驗中，於10 mL之反溶劑中迅速地添加10 mL之儲備原液。於某些情況下，隨即添加另一份量之反溶劑(20 mL)。將所得之懸浮液於室溫攪拌一段時間。將所得之固體過濾出，將其乾燥(於空氣或氮氣氣流中)，並以粉末X光繞射及/或傅立葉轉換光譜檢測其特徵。 In each precipitation experiment, 10 mL of the stock solution was quickly added to 10 mL of the anti-solvent. In some cases, another amount of anti-solvent (20 mL) was added. The resulting suspension was stirred at room temperature for a period of time. The resulting solid is filtered off, dried (in a stream of air or nitrogen) and characterized by powder X-ray diffraction and/or Fourier transform spectroscopy.

實驗條件與結果之細節總結於下表。所得形式之特徵細節參見「分析」段落。 The experimental conditions and details of the results are summarized in the table below. See the "Analysis" section for details on the features of the resulting form.

1)粗體字：混合物中之主要成分 1) Bold characters: the main components in the mixture

由上方表格中顯見A、D、F與G為使用快速沉澱技術方式時所獲得之主要形式。於數個樣本中，於A或F中發現小量之B形 式混合在其中。實驗中未發現非晶形。 It is apparent from the above table that A, D, F and G are the main forms obtained when using the rapid precipitation technique. A small number of B shapes were found in A or F in several samples. Mix in it. No amorphous form was found in the experiment.

實例3 Example 3

懸浮平衡實驗 Suspension balance experiment

下列實驗設計之目的為識別(熱力學)更穩定之同素異形體。於各懸浮平衡實驗中，起始原物質係懸浮於溶媒中，並經數日攪拌之攪拌。將所得之固體過濾出，將其乾燥(於真空狀態或於空氣中)，並以粉末X光繞射及/或傅立葉轉換拉曼光譜檢定其特徵。 The purpose of the following experimental design is to identify (thermodynamically) more stable allotropes. In each suspension equilibrium experiment, the starting material was suspended in a solvent and stirred with stirring for several days. The resulting solid is filtered off, dried (in a vacuum or in air) and characterized by powder X-ray diffraction and/or Fourier transform Raman spectroscopy.

實驗條件與結果之細節總結於下表。所得形式之特徵細節參見「分析」段落。 The experimental conditions and details of the results are summarized in the table below. See the "Analysis" section for details on the features of the resulting form.

1)將溶媒混合物加至其它同素異形體混合物前，先令其達到晶形B飽和狀態 1) Before adding the solvent mixture to the other allotrope mixture, let it reach the crystal form B saturation state.

由上方表格中顯見除了一個例外，所獲得之形式皆為晶形B。甚至晶形A、B、C、D與F之混合物亦被轉化為晶形B，顯示晶形B係室溫中最穩定之非溶劑化物形式。僅有存在於水之晶形A懸浮液未在7天內被轉化成另一形式。其原因可能為晶形A於水之溶解度極低(1.21 mg/L)，即其平衡時間極長。 It is apparent from the above table that, with one exception, the form obtained is Form B. Even a mixture of Forms A, B, C, D and F was also converted to Form B, showing Form B being the most stable unsolvated form at room temperature. Only the crystalline Form A suspension present in water was not converted to another form within 7 days. The reason may be that the solubility of crystal form A in water is extremely low (1.21 mg/L), that is, its equilibrium time is extremely long.

實例4 Example 4

汽擴散實驗 Vapor diffusion experiment

此實驗設計之目的為培養適用於X光單晶繞射之單晶形式。於各實驗中，製備晶形B不飽和之溶液，並將其暴露於含反溶劑之氣氛中。擴散過程會降低其溶解度，隨後會產生結晶反應。 The purpose of this experimental design was to develop a single crystal form suitable for X-ray single crystal diffraction. In each experiment, a solution of Form B unsaturation was prepared and exposed to an atmosphere containing an anti-solvent. The diffusion process reduces its solubility and subsequently produces a crystallization reaction.

使用兩種不同溫度之兩種不同溶媒/反溶劑系統。 Two different solvent/antisolvent systems are used at two different temperatures.

為實驗4-1)及4-2)製備一儲備原液： Prepare a stock solution for experiments 4-1) and 4-2):

將110 mg之晶形B懸浮於40 mL之N-甲基-2-吡咯啶酮中。將所得之懸浮液於室溫攪拌2小時，並以過濾方式去除殘留之小量固體(0.20 μm)。 110 mg of Form B was suspended in 40 mL of N-methyl-2-pyrrolidone. The resulting suspension was stirred at room temperature for 2 hours and the residual small solid (0.20 m) was removed by filtration.

為實驗4-3)及4-4)製備一儲備原液： Prepare a stock solution for Runs 4-3) and 4-4):

將29 mg之晶形B懸浮於20 mL之二氯甲烷中。將所得之懸浮液於室溫攪拌2小時，並以過濾方式去除殘留之大量固體(0.20 μm)。 29 mg of Form B was suspended in 20 mL of dichloromethane. The resulting suspension was stirred at room temperature for 2 hours, and a large amount of residual solid (0.20 μm) was removed by filtration.

於各汽擴散實驗中，將10 mL之相應溶液暴露於不同溫度(室溫或4℃)之含反溶劑氣氛中，暴露之時間不同。以X光單晶繞射分析所得之固體。由X光單晶繞射數據計算相應之粉末X光繞射型態，並與於不同晶形(由其它實驗獲得)中測量所得之粉末X光 繞射光譜進行比較。 In each vapor diffusion experiment, 10 mL of the corresponding solution was exposed to an anti-solvent atmosphere at different temperatures (room temperature or 4 ° C) for different exposure times. The resulting solid was analyzed by X-ray single crystal diffraction. The corresponding powder X-ray diffraction pattern is calculated from the X-ray single crystal diffraction data, and the powder X-rays measured in different crystal forms (obtained from other experiments) are obtained. The diffraction spectrum is compared.

實驗條件與結果之細節總結於下表。所得形式之特徵細節參見「分析」段落。 The experimental conditions and details of the results are summarized in the table below. See the "Analysis" section for details on the features of the resulting form.

1)藉由比較晶形之計算所得之粉末X光繞射光譜與測量所得之粉末X光繞射光譜(如於其它實驗獲得之光譜)判定；2)參見以下註解。 1) Determined by comparing the calculated powder X-ray diffraction spectrum of the crystal form with the measured powder X-ray diffraction spectrum (as obtained from other experiments); 2) See the following note.

實驗4-3)之樣本最可能與晶形A相對應。樣本4-4)之計算所得之粉末X光繞射型態與晶形D之量測所得之粉末X光繞射型態相似。然而，因X光單晶繞射與粉末X光繞射實驗係於不同溫度進行，無法十分確定地判定該樣本的確與晶形D相對應。 The sample of Experiment 4-3) is most likely to correspond to Form A. The calculated powder X-ray diffraction pattern of Sample 4-4) is similar to the powder X-ray diffraction pattern obtained by the measurement of Form D. However, since the X-ray single crystal diffraction and the powder X-ray diffraction experiment were carried out at different temperatures, it was not possible to determine with certainty that the sample did correspond to the crystal form D.

實例5 Example 5

蒸發實驗 Evaporation experiment

將46 mg之晶形B以40 mL之二氯甲烷溶解，以製備一晶形B不飽和之溶液。將溶媒於真空狀態蒸發45分鐘。將殘留之固體於真空狀態乾燥2小時，以獲得晶形B。 46 mg of Form B was dissolved in 40 mL of dichloromethane to prepare a solution of Form B unsaturated. The solvent was evaporated under vacuum for 45 minutes. The residual solid was dried under vacuum for 2 hours to obtain crystal form B.

實例6 Example 6

對以瑪瑙乳缽進行研磨所造成之機械應力影響進行分析。 Analysis of the effects of mechanical stress caused by grinding with agate mortar.

6-1)將一晶形A之樣本以瑪瑙乳缽研磨10分鐘。以粉末X光繞射檢測所得固體之特徵。除了可能因研磨後之容積密度較高所造成之略為增加之背景訊號之外，未發現其與研磨前之粉末X光繞射光譜有顯著差異。研磨後未觀察到額外之波峰，即10分鐘之研磨未顯著地將晶形A轉化為另一形式。 6-1) A sample of Form A was ground in an agate mortar for 10 minutes. The characteristics of the obtained solid were examined by powder X-ray diffraction. In addition to the slightly increased background signal due to the higher bulk density after grinding, it was found to be significantly different from the powder X-ray diffraction spectrum before grinding. No additional peaks were observed after milling, i.e., 10 minutes of milling did not significantly convert Form A to another form.

6-2)將一晶形A之樣本以瑪瑙乳缽研磨10分鐘。以粉末X光繞射檢定所得固體之特徵。除了可能因研磨後之容積密度較高所造成之略為增加之背景訊號，及可能因研磨後晶體大小縮減所造成之略微增寬之波峰以外，未發現其與研磨前之粉末X光繞射光譜有顯著差異。研磨後未觀察到額外之波峰，即10分鐘之研磨未顯著地將晶形B轉化為另一形式。 6-2) A sample of Form A was ground in an agate mortar for 10 minutes. The characteristics of the obtained solid were examined by powder X-ray diffraction. In addition to the slight increase in background signal due to the higher bulk density after grinding, and the slight widening of the peak due to the reduction in crystal size after grinding, the powder X-ray diffraction spectrum before and after grinding was not found. There are significant differences. No additional peaks were observed after milling, i.e., 10 minutes of milling did not significantly convert Form B to another form.

分析-核磁共振 Analysis - nuclear magnetic resonance

晶形A、B與C之氫-核磁共振光譜符合(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽之結構。相較於自由鹼之光譜，該氫-核磁共振光譜顯示峰值位移，其亦代表鹽類之形成。 The hydrogen-nuclear magnetic resonance spectra of crystal forms A, B and C correspond to (1r, 4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H- The structure of spiro [cyclohexane-1,1'-pyrano[3,4,b]indole-4-amine hydrochloride. The hydrogen-nuclear magnetic resonance spectrum shows a peak shift compared to the spectrum of the free base, which also represents the formation of salts.

分析-元素分析 Analysis-element analysis

晶形A Crystal form A

元素成分分析之結果如表5所示。其證實鹽類之形成。 The results of the elemental composition analysis are shown in Table 5. It confirms the formation of salts.

晶形B Crystal Form B

元素成分分析之結果如表6所示。其證實鹽類之形成。 The results of the elemental composition analysis are shown in Table 6. It confirms the formation of salts.

1)假設無水存在之情況下之計算值；2)假設含有0.44%之水分存在之情況下之計算值。 1) Calculated value assuming water is absent; 2) Calculated value assuming 0.44% of water is present.

晶形C Crystal form C

元素成分分析係以實驗1至4之樣本進行，即利用C為主要成分及其它物質之混合物。元素成分分析之結果如表7所示。其不符合假設之化學計量。然而，該樣本於實驗中出現失重，即於元素分析中無法精確地秤重。 The elemental composition analysis was carried out using the samples of Experiments 1 to 4, that is, using C as a main component and a mixture of other substances. The results of the elemental composition analysis are shown in Table 7. It does not meet the assumed stoichiometry. However, the sample showed weightlessness in the experiment, which was impossible to accurately weigh in elemental analysis.

1)假設無水存在之情況下之計算值；2)假設含有33.56%之水分存在之情況下之計算值。 1) Calculated value assuming no water is present; 2) Calculated value assuming 33.56% of water is present.

分析-X光粉末繞射 Analysis - X-ray powder diffraction

X光粉末繞射分析係以Philips X'pert PW 3040 X光粉末繞射儀於傳輸幾何進行，所使用之單晶化CuKα輻射係以鍺單晶進行。d-距離係由2θ值於計算所得，其係以波長1.54060 Å為基礎。d-值分析係以EVA版本10,0,0,0.之軟體進行。利用軟體移除CuKα2，僅列出高達35°之2θ值。通常2θ值於2θ中之誤差率為±0.2°。因此d-距離數值之實驗誤差取決於波峰之位置。 The X-ray powder diffraction analysis was carried out in a transmission geometry using a Philips X'pert PW 3040 X-ray powder diffractometer, and the single crystal CuKα radiation used was carried out as a germanium single crystal. The d-distance is calculated from the 2θ value and is based on a wavelength of 1.54060 Å. The d-value analysis was performed with software of EVA version 10, 0, 0, 0. Using the software to remove CuKα 2 , only 2θ values up to 35° are listed. Usually, the error rate of the 2θ value in 2θ is ±0.2°. Therefore, the experimental error of the d-distance value depends on the position of the peak.

可利用布拉格定律，由2θ值計算出d-距離之數值。 The value of the d-distance can be calculated from the 2θ value using Bragg's law.

除了施加些許壓力以獲得平整表面之外，樣本之計算未經任何特別處理。使用周圍空氣氣氛。為防止因儀器造成之汙染，將樣本以聚醯亞胺箔(capton foil)密封。 The calculation of the sample was not subject to any special treatment except that a slight pressure was applied to obtain a flat surface. Use the surrounding air atmosphere. To prevent contamination from the instrument, the sample was sealed with a capton foil.

晶形ACrystal form A

第1a圖顯示晶形A之粉末X光繞射型態。表8顯示晶形A之波峰列表。2θ值於2θ中之不確定性為±0.2°；rel.I(relative intensity)代表相應波峰之相對強度。相對強度之最大值為100。 Figure 1a shows the powder X-ray diffraction pattern of Form A. Table 8 shows a list of peaks of Form A. The uncertainty of the 2θ value in 2θ is ±0.2°; rel.I (relative intensity) represents the relative intensity of the corresponding peak. The maximum relative intensity is 100.

晶形BCrystal Form B

第1b圖顯示晶形B之粉末X光繞射型態。表9顯示晶形B之波峰列表。2θ值於2θ中之不確定性為±0.2°；rel.I代表相應波峰之相對強度。相對強度之最大值為100。 Figure 1b shows the powder X-ray diffraction pattern of Form B. Table 9 shows a list of peaks of Form B. The uncertainty of the 2θ value in 2θ is ±0.2°; rel.I represents the relative intensity of the corresponding peak. The maximum relative intensity is 100.

晶形CCrystal form C

第1c圖顯示晶形C之粉末X光繞射型態。表10顯示晶形C之波峰列表。2θ值於2θ中之不確定性為±0.2°；rel.I代表相應波峰之相對強度。相對強度之最大值為100。 Figure 1c shows the powder X-ray diffraction pattern of Form C. Table 10 shows a list of peaks for Form C. The uncertainty of the 2θ value in 2θ is ±0.2°; rel.I represents the relative intensity of the corresponding peak. The maximum relative intensity is 100.

晶形DCrystal form D

第1d圖顯示晶形D之粉末X光繞射型態。表11顯示晶形D之波峰列表。2θ值於2θ中之不確定性為±0.2°；rel.I代表相應波峰之相對強度。相對強度之最大值為100。 Figure 1d shows the powder X-ray diffraction pattern of Form D. Table 11 shows a list of peaks of Form D. The uncertainty of the 2θ value in 2θ is ±0.2°; rel.I represents the relative intensity of the corresponding peak. The maximum relative intensity is 100.

晶形ECrystal form E

第1e圖顯示晶形E之粉末X光繞射型態。表12顯示晶形E之波峰列表。2θ值於2θ中之不確定性為±0.2°；rel.I代表相應波峰之相對強度。相對強度之最大值為100。 Figure 1e shows the powder X-ray diffraction pattern of Form E. Table 12 shows a list of peaks of Form E. The uncertainty of the 2θ value in 2θ is ±0.2°; rel.I represents the relative intensity of the corresponding peak. The maximum relative intensity is 100.

晶形FCrystal form F

第1f圖顯示晶形F之粉末X光繞射型態。表13顯示晶形F之波峰列表。2θ值於2θ中之不確定性為±0.2°；rel.I代表相應波峰之相對強度。相對強度之最大值為100。 Figure 1f shows the powder X-ray diffraction pattern of Form F. Table 13 shows a list of peaks of Form F. The uncertainty of the 2θ value in 2θ is ±0.2°; rel.I represents the relative intensity of the corresponding peak. The maximum relative intensity is 100.

晶形GCrystal form G

第1g圖顯示晶形G之粉末X光繞射型態。表14顯示晶形G之波峰列表。2θ值於2θ中之不確定性為±0.2°；rel.I代表相應波峰之相對強度。相對強度之最大值為100。 Figure 1g shows the powder X-ray diffraction pattern of Form G. Table 14 shows a list of peaks of Form G. The uncertainty of the 2θ value in 2θ is ±0.2°; rel.I represents the relative intensity of the corresponding peak. The maximum relative intensity is 100.

分析-傳立葉轉換拉曼光譜 Analysis-transfer leaf conversion Raman spectroscopy

傳立葉轉換拉曼光譜係以Bruker RFS100拉曼光譜儀紀錄(Nd-YAG 100 mW雷射，1064 nm之激發波長，100 mW之雷射功率，鍺偵測器，64掃描，25-3500 cm-1，2 cm-1之解析度)。 The ray-converted Raman spectroscopy was recorded on a Bruker RFS100 Raman spectrometer (Nd-YAG 100 mW laser, 1064 nm excitation wavelength, 100 mW laser power, 锗 detector, 64 scans, 25-3500 cm -1 , resolution of 2 cm -1 ).

第2a圖顯示晶形A之拉曼光譜。 Figure 2a shows the Raman spectrum of Form A.

第2b圖顯示晶形B之拉曼光譜。 Figure 2b shows the Raman spectrum of Form B.

第2c圖顯示晶形C之拉曼光譜。 Figure 2c shows the Raman spectrum of Form C.

第2d圖顯示晶形D之拉曼光譜。 Figure 2d shows the Raman spectrum of Form D.

第2e圖顯示晶形E之拉曼光譜。 Figure 2e shows the Raman spectrum of Form E.

第2f圖顯示晶形F之拉曼光譜。 Figure 2f shows the Raman spectrum of Form F.

第2g圖顯示晶形G之拉曼光譜。 Figure 2g shows the Raman spectrum of Form G.

拉曼波峰表係使用OPUS軟體3.1版所建立：3,0,17 (20010216)。波峰檢出功能之敏感度係選擇可偵測出大部分波峰者(通常介於0.5%與3%之間)。意外地歸因於峰值及和明顯地為噪音之特徵係以人工方式剔除。波峰係列於介於3200 cm-1與150 cm-1之間之光譜區。強度分級方面使用了絕對強度，並將最強波峰縮放至約100%。其分級如下：非常強(vs)：I>80%；強(s)：80%I>60%；中(m)：60%I>40%；弱(w)：40%I>20%；與非常弱(vw)：20%I。 The Raman peak table was established using OPUS software version 3.1: 3,0,17 (20010216). The sensitivity of the peak detection function is selected to detect most of the peaks (usually between 0.5% and 3%). Features that are unexpectedly attributed to peaks and are clearly noise are manually rejected. The peak series is in the spectral region between 3200 cm -1 and 150 cm -1 . Absolute intensity is used in intensity grading and the strongest peak is scaled to approximately 100%. Its rating is as follows: very strong (vs): I>80%; strong (s): 80% I>60%; medium (m): 60% I>40%; weak (w): 40% I>20%; and very weak (vw): 20% I.

晶形ACrystal form A

3201(vw)、3071(m)、3041(w)、3020(vw)、2986(w)、2958(s)、2935(w)、2907(w)、2882(w)、2858(vw)、2847(vw)、2811(vw)、2542(vw)、1625(vw)、1600(vw)、1582(w)、1554(vs)、1470(w)、1441(w)、1372(w)、1353(vw)、1316(w)、1295(w)、1268(vw)、1234(vw)、1208(vw)、1201(vw)、1175(vw)、1156(w)、1128(vw)、1112(vw)、1095(vw)、1061(vw)、1049(vw)、1034(w)、1003(m)、965(vw)、926(w)、914(w)、885(vw)、869(vw)、842(vw)、824(vw)、789(vw)、712(vw)、691(w)、660(vw)、642(vw)、621(vw)、597(vw)、554(vw)、536(vw)、524(vw)、512(vw)、483(vw)、451(vw)、408(vw)。 3201 (vw), 3071 (m), 3041 (w), 3020 (vw), 2986 (w), 2958 (s), 2935 (w), 2907 (w), 2882 (w), 2858 (vw), 2847 (vw), 2811 (vw), 2542 (vw), 1625 (vw), 1600 (vw), 1582 (w), 1554 (vs), 1470 (w), 1441 (w), 1372 (w), 1353 (vw), 1316 (w), 1295 (w), 1268 (vw), 1234 (vw), 1208 (vw), 1201 (vw), 1175 (vw), 1156 (w), 1128 (vw), 1112 (vw), 1095 (vw), 1061 (vw), 1049 (vw), 1034 (w), 1003 (m), 965 (vw), 926 (w), 914 (w), 885 (vw), 869 (vw), 842 (vw), 824 (vw), 789 (vw), 712 (vw), 691 (w), 660 (vw), 642 (vw), 621 (vw), 597 (vw), 554 (vw), 536 (vw), 524 (vw), 512 (vw), 483 (vw), 451 (vw), 408 (vw).

晶形BCrystal Form B

3069(m)、3054(m)、3034(w)、2992(s)、2958(w)、2931(w)、2922(w)、2906(w)、2870(w)、2845(vw)、1628(vw)、1583(s)、1569(vs)、1481(w)、1463(w)、1436(w)、1374(w)、1352(vw)、1300(s)、1265(vw)、1222(vw)、1216(vw)、1199(vw)、1174(vw)、1136(vw)、1120(w)、1073(vw)、1047(vw)、1035(vw)、1028(vw)、1001(m)、984(vw)、957(vw)、928(vw)、919(m)、888(vw)、873 (vw)、856(vw)、828(vw)、820(vw)、808(vw)、786(vw)、768(vw)、710(vw)、683(w)、628(vw)、620(vw)、606(vw)、598(vw)、568(vw)、557(vw)、540(vw)、518(vw)、491(w)；466(vw)、450(vw)、430(vw)、397(vw)、371(vw)、279(vw)、255(vw)、208(w)、183(m)、160(w)。 3069 (m), 3054 (m), 3034 (w), 2992 (s), 2958 (w), 2931 (w), 2922 (w), 2906 (w), 2870 (w), 2845 (vw), 1628 (vw), 1583 (s), 1569 (vs), 1481 (w), 1463 (w), 1436 (w), 1374 (w), 1352 (vw), 1300 (s), 1265 (vw), 1222 (vw), 1216 (vw), 1199 (vw), 1174 (vw), 1136 (vw), 1120 (w), 1073 (vw), 1047 (vw), 1035 (vw), 1028 (vw), 1001 (m), 984 (vw), 957 (vw), 928 (vw), 919 (m), 888 (vw), 873 (vw), 856 (vw), 828 (vw), 820 (vw), 808 (vw), 786 (vw), 768 (vw), 710 (vw), 683 (w), 628 (vw), 620 (vw), 606 (vw), 598 (vw), 568 (vw), 557 (vw), 540 (vw), 518 (vw), 491 (w); 466 (vw), 450 (vw), 430 (vw), 397 (vw), 371 (vw), 279 (vw), 255 (vw), 208 (w), 183 (m), 160 (w).

晶形CCrystal form C

3072(m)、3045(vw)、3031(vw)、2994(vw)、2959(w)、2927(vw)、2901(vw)、2880(vw)、2842(vw)、1628(vw)、1600(w)、1584(s)、1567(vs)、1481(w)、1464(w)、1454(w)、1432(w)、1374(w)、1359(vw)、1301(m)、1267(vw)、1219(w)、1200(vw)、1167(vw)、1136(vw)、1114(w)、1076(vw)、1055(vw)、1028(w)、1000(m)、986(vw)、954(vw)、925(m)、918(m)、889(vw)；829(w)、786(vw)、772(vw)、710(vw)、685(m)、628(w)、620(w)、600(w)、567(vw)、538(vw)、516(vw)、490(w)、471(vw)、429(vw)、395(vw)、370(w)、322(vw)、266(w)、253(w)、208(w)、177(s)、158(m)。 3072 (m), 3045 (vw), 3031 (vw), 2994 (vw), 2959 (w), 2927 (vw), 2901 (vw), 2880 (vw), 2842 (vw), 1628 (vw), 1600 (w), 1584 (s), 1567 (vs), 1481 (w), 1464 (w), 1454 (w), 1432 (w), 1374 (w), 1359 (vw), 1301 (m), 1267 (vw), 1219 (w), 1200 (vw), 1167 (vw), 1136 (vw), 1114 (w), 1076 (vw), 1055 (vw), 1028 (w), 1000 (m), 986 (vw), 954 (vw), 925 (m), 918 (m), 889 (vw); 829 (w), 786 (vw), 772 (vw), 710 (vw), 685 (m), 628 (w), 620 (w), 600 (w), 567 (vw), 538 (vw), 516 (vw), 490 (w), 471 (vw), 429 (vw), 395 (vw), 370 (w), 322 (vw), 266 (w), 253 (w), 208 (w), 177 (s), 158 (m).

晶形DCrystal form D

3071(vs)、3038(w)、2981(s)、2957(vs)、2912(s)、2875(m)、2845(w)、1627(w)、1573(vs)、1567(vs)、1466(m)、1443(m)、1374(m)、1355(w)、1339(vw)、1308(m)、1299(s)、1263(w)；1250(vw)、1217(w)、1197(w)、1183(vw)、1161(w)、1134(vw)、1116(w)、1074(vw)、1045(w)；1035(w)、1028(w)、1004(s)、983(w)、953(vw)、919(s)、887(w)、869(vw)、829(m)、787(vw)；771(vw)、712(vw)、686(s)、676(w)、629(w)、620(w)、600(m)、569(vw)、557(vw)、538(vw)；517(w)、490(w)、468(vw)、429(w)、401(vw)、 392(w)、370(w)、317(vw)、278(w)、252(m)、206(m)、180(vs)、172(vs)、161(vs)。 3071 (vs), 3038 (w), 2981 (s), 2957 (vs), 2912 (s), 2875 (m), 2845 (w), 1627 (w), 1573 (vs), 1567 (vs), 1466 (m), 1443 (m), 1374 (m), 1355 (w), 1339 (vw), 1308 (m), 1299 (s), 1263 (w); 1250 (vw), 1217 (w), 1197(w), 1183(vw), 1161(w), 1134(vw), 1116(w), 1074(vw), 1045(w); 1035(w), 1028(w), 1004(s), 983 (w), 953 (vw), 919 (s), 887 (w), 869 (vw), 829 (m), 787 (vw); 771 (vw), 712 (vw), 686 (s), 676 (w), 629 (w), 620 (w), 600 (m), 569 (vw), 557 (vw), 538 (vw); 517 (w), 490 (w), 468 (vw), 429(w), 401(vw), 392 (w), 370 (w), 317 (vw), 278 (w), 252 (m), 206 (m), 180 (vs), 172 (vs), 161 (vs).

晶形ECrystal form E

3069(vs)、3048(w)、3031(vw)、2986(w)、2963(s)、2889(w)、2873(w)、2855(w)、1630(vw)、1582(m)、1569(vs)、1494(vw)、1465(w)、1441(w)、1376(w)、1353(vw)、1308(m)、1299(m)、1267(vw)、1220(w)、1200(w)、1166(vw)、1142(vw)、1133(vw)、1117(vw)、1107(vw)；1076(vw)、1047(vw)、1029(w)、1019(vw)、1003(m)、993(vw)、983(vw)、952(vw)、917(m)、889(vw)、870(vw)、854(vw)、836(m)、786(vw)、713(vw)、686(m)、676(vw)、629(vw)、619(vw)；599(w)、568(vw)、558(vw)、538(vw)、517(vw)、491(w)、471(vw)、433(vw)、395(vw)、369(w)、317(vw)、287(vw)、253(w)、211(w)、176(m)、160(m)。 3069 (vs), 3048 (w), 3031 (vw), 2986 (w), 2963 (s), 2889 (w), 2873 (w), 2855 (w), 1630 (vw), 1582 (m), 1569 (vs), 1494 (vw), 1465 (w), 1441 (w), 1376 (w), 1353 (vw), 1308 (m), 1299 (m), 1267 (vw), 1220 (w), 1200 (w), 1166 (vw), 1142 (vw), 1133 (vw), 1117 (vw), 1107 (vw); 1076 (vw), 1047 (vw), 1029 (w), 1019 (vw), 1003 (m), 993 (vw), 983 (vw), 952 (vw), 917 (m), 889 (vw), 870 (vw), 854 (vw), 836 (m), 786 (vw), 713 (vw), 686 (m), 676 (vw), 629 (vw), 619 (vw); 599 (w), 568 (vw), 558 (vw), 538 (vw), 517 (vw), 491(w), 471(vw), 433(vw), 395(vw), 369(w), 317(vw), 287(vw), 253(w), 211(w), 176(m), 160 (m).

晶形FCrystal form F

3070(vs)、3029(w)、2979(s)、2954(m)、2942(w)、2895(w)、2840(vw)、1629(vw)、1585(vs)、1573(s)、1486(vw)、1468(w)、1458(w)、1434(w)、1368(vw)、1295(s)、1264(vw)、1217(w)、1201(vw)、1170(vw)、1132(vw)、1110(w)、1047(vw)、1030(w)、1003(m)、980(vw)、917(m)、888(vw)、829(vw)、786(vw)、769(vw)、707(vw)、683(w)、620(vw)、598(w)、568(vw)、538(vw)、515(vw)、488(vw)、436(vw)、390(vw)、367(vw)、273(vw)、254(w)、206(m)、174(m)、160(s)。 3070 (vs), 3029 (w), 2979 (s), 2954 (m), 2942 (w), 2895 (w), 2840 (vw), 1629 (vw), 1585 (vs), 1573 (s), 1486 (vw), 1468 (w), 1458 (w), 1434 (w), 1368 (vw), 1295 (s), 1264 (vw), 1217 (w), 1201 (vw), 1170 (vw), 1132 (vw), 1110 (w), 1047 (vw), 1030 (w), 1003 (m), 980 (vw), 917 (m), 888 (vw), 829 (vw), 786 (vw), 769 (vw), 707 (vw), 683 (w), 620 (vw), 598 (w), 568 (vw), 538 (vw), 515 (vw), 488 (vw), 436 (vw), 390 (vw), 367 (vw), 273 (vw), 254 (w), 206 (m), 174 (m), 160 (s).

晶形GCrystal form G

3164(vw)、3089(vw)、3077(vw)、3053(w)、3019(vw)、3006 (vw)、2986(vw)、1636(vw)、1582(vw)、1512(vw)、1446(vw)、1422(vw)、1361(vw)、1304(vw)、1242(vw)、1193(vw)；1146(vw)、1070(vw)、1028(vs)、1005(vw)、986(vw)、894(vw)、846(vw)、835(vw)、774(vw)；700(vw)、654(vw)、642(vw)、623(vw)、560(vw)、445(vw)、293(vw)、274(w)、200(vw)。 3164 (vw), 3089 (vw), 3077 (vw), 3053 (w), 3019 (vw), 3006 (vw), 2986 (vw), 1636 (vw), 1582 (vw), 1512 (vw), 1446 (vw), 1422 (vw), 1361 (vw), 1304 (vw), 1242 (vw), 1193 (vw); 1146 (vw), 1070 (vw), 1028 (vs), 1005 (vw), 986 (vw), 894 (vw), 846 (vw), 835 (vw), 774 (vw); 700 (vw), 654 (vw), 642 (vw), 623 (vw), 560 (vw), 445 (vw), 293 (vw), 274 (w), 200 (vw).

分析-示差掃描熱量分析 Analysis - Differential Scanning Thermal Analysis

示差掃描熱量分析：參考儀器為Perkin Elmer DSC 7。除非另有註明，樣本係密封之金坩堝中進行秤重。量測係於氮氣氣流下，於-50℃至高達350℃之溫度範圍進行，其加熱速率為10℃/分鐘。除非另有註明，於示差掃描熱量分析中指定之溫度為最大峰值之溫度。 Differential Scanning Thermal Analysis: The reference instrument was Perkin Elmer DSC 7. Unless otherwise noted, the sample is weighed in a sealed metal. The measurement was carried out under a nitrogen gas stream at a temperature ranging from -50 ° C to as high as 350 ° C, and the heating rate was 10 ° C / min. Unless otherwise noted, the temperature specified in the differential scanning calorimetry is the maximum peak temperature.

於下表F中，「△H」代表「比熱(specific heat)」，及「波峰(peak)」代表於一給定之尖峰溫度中觀測到之熱事件。 In Table F below, "△H" stands for "specific heat" and "peak" represents a thermal event observed at a given peak temperature.

分析-熱重-傅立葉轉換紅外線連用光譜 Analysis - Thermogravimetry - Fourier Transform Infrared Spectroscopy

熱重-傅立葉轉換紅外線連用光譜係利用Netzsch生產之Thermo-Microwaage TG 209及Bruker生產之傅立葉光譜儀Vector 22(鋁坩堝(開放式或有微孔))，於氮氣氣氛下紀錄，(其加熱速率為10℃/分鐘，由25至350℃)。 The thermogravimetry-Fourier transform infrared spectroscopy spectrum was recorded using a Thermo-Microwaage TG 209 manufactured by Netzsch and a Fourier spectrometer Vector 22 (aluminum crucible (open or microporous)) manufactured by Bruker under a nitrogen atmosphere. 10 ° C / min, from 25 to 350 ° C).

以晶形A樣本進行之熱重-傅立葉轉換紅外線連用光譜分析， 顯示於50至250℃之溫度範圍內未出現顯著之失重現象(-0.06%)，其代表晶形A不含密封溶媒(enclosed solvent)(即其為一非溶劑化物)。 Thermogravimetry-Fourier transform infrared spectroscopy with spectral A sample, No significant weight loss (-0.06%) was observed in the temperature range of 50 to 250 °C, which represents that Form A does not contain an enclosed solvent (i.e., it is an unsolvate).

以晶形B樣本進行之熱重-傅立葉轉換紅外線連用光譜分析，顯示於室溫至250℃之溫度範圍內之失重率係約0.5%。重量流失可歸因於水。於溫度高於270℃時觀察到分解現象。基於這些量測，晶形B為一非溶劑化物。 The thermogravimetry-Fourier transform infrared spectroscopy analysis using the crystal form B sample showed that the weight loss rate in the temperature range from room temperature to 250 ° C was about 0.5%. Weight loss can be attributed to water. Decomposition was observed at temperatures above 270 °C. Based on these measurements, Form B is an unsolvate.

以晶形C樣本進行之熱重-傅立葉轉換紅外線連用光譜分析，顯示24.7%之重量流失。此失重率於約115℃時最強烈，且可歸因於水(七水合物：23.3%；八水合物：25.8%)。於溫度高於270℃時觀察到分解現象。基於這些量測，晶形C為一水合物。 The thermogravimetry-Fourier transform infrared spectroscopy using a crystal form C sample showed a loss of 24.7% by weight. This weight loss rate is most intense at about 115 ° C and is attributable to water (heptahydrate: 23.3%; octahydrate: 25.8%). Decomposition was observed at temperatures above 270 °C. Based on these measurements, Form C is a monohydrate.

以晶形D樣本進行之熱重-傅立葉轉換紅外線連用光譜分析，顯示於室溫至240℃之溫度範圍內之失重率為1.1至1.4%。此流失之重量可歸因於水。於溫度高於270℃時觀察到分解現象。基於這些量測，晶形D為一溶劑化物。 The thermogravimetry-Fourier transform infrared spectroscopy analysis using the crystal form D sample showed a weight loss ratio of 1.1 to 1.4% in the temperature range from room temperature to 240 °C. The weight of this loss can be attributed to water. Decomposition was observed at temperatures above 270 °C. Based on these measurements, Form D is a solvate.

以晶形E樣本進行之熱重-傅立葉轉換紅外線連用光譜分析，顯示於室溫至200℃之溫度範圍內之失重率為15.1%。此失重率於約110℃時最強烈，且可歸因於二氧陸圜(單溶劑化物(monosolvate：17.5%)。於溫度高於270℃時觀察到分解現象。 The thermogravimetry-Fourier transform infrared spectroscopy analysis using the crystal form E sample showed a weight loss ratio of 15.1% in the temperature range from room temperature to 200 °C. This weight loss rate is most intense at about 110 ° C and is attributable to dioxane (monosolvate: 17.5%). Decomposition is observed at temperatures above 270 °C.

以晶形F樣本進行之熱重-傅立葉轉換紅外線連用光譜分析，顯示於室溫至250℃之溫度範圍內之失重率為0.2%。流失之重量可歸因於水。於溫度高於270℃時觀察到分解現象。基於這些量測，晶形F為一非溶劑化物。 The thermogravimetry-Fourier transform infrared spectroscopy analysis using the crystal form F sample showed a weight loss rate of 0.2% in the temperature range from room temperature to 250 °C. The weight lost can be attributed to water. Decomposition was observed at temperatures above 270 °C. Based on these measurements, Form F is an unsolvate.

以晶形G樣本進行之熱重-傅立葉轉換紅外線連用光譜分析，顯示於70至200℃之溫度範圍內之失重率為7.4%。此失重率於約170℃時最強烈，且可歸因於水。於約280℃時觀測到45.2%之急遽、階段性之重量流失，且可歸因於啶。此步驟遠高於啶之 沸點(115℃)，代表啶係緊緊地連結在一起。於高達350℃時未觀察到分解現象。 The thermogravimetry-Fourier transform infrared spectroscopy analysis using the crystalline G sample showed a weight loss rate of 7.4% in the temperature range of 70 to 200 °C. This weight loss rate is most intense at about 170 ° C and is attributable to water. A 45.2% rapid, phased weight loss was observed at about 280 °C and was attributable to the pyridine. This step is much higher than the pyridine The boiling point (115 ° C), which means that the pyridine system is tightly linked together. No decomposition was observed up to 350 °C.

分析-動態濕氣吸附 Analysis - Dynamic moisture adsorption

晶形A與B之特徵係使用Projekt Messtechnik SPS 11-100n多樣本濕氣吸附分析儀以動態濕氣吸附進行分析。於該動態濕氣吸附分析中，將各樣本置放於一鋁坩堝中，並於啟動預先定義之濕度程序前將其於50%之相對溼度中平衡，並於啟動期間判定樣本之重量變化。 The characteristics of Forms A and B were analyzed by dynamic moisture adsorption using a Projekt Messtechnik SPS 11-100n multi-sample moisture adsorption analyzer. In the dynamic moisture adsorption analysis, each sample was placed in an aluminum crucible and equilibrated in 50% relative humidity prior to initiating a predefined humidity program, and the weight change of the sample was determined during startup.

雖然測量吸濕性之方法有些微不同，其係根據歐洲藥典做如下分級：吸濕性極強(vh)：增加之質量15%；具吸濕性(h)：增加之質量小於15%但等於或大於2%；具些微吸濕性(sh)：增加之質量小於2%但等於或大於0.2%；不具吸濕性(nh)：增加之質量小於0.2%；易潮解(d)：所吸收之水分足以形成液體。 Although the method of measuring hygroscopicity is slightly different, it is graded according to the European Pharmacopoeia: very hygroscopic (vh): increased quality 15%; hygroscopic (h): increased mass less than 15% but equal to or greater than 2%; slightly hygroscopic (sh): increased mass less than 2% but equal to or greater than 0.2%; non-hygroscopic (nh): the mass of the addition is less than 0.2%; the deliquescent (d): the absorbed water is sufficient to form a liquid.

晶形ACrystal form A

含兩個循環之動態濕氣吸附分析係根據下列程式，以晶形A之樣本進行：於50%之相對溼度中2小時；50%→0%之相對溼度(10%/小時)；於0%之相對溼度中5小時；0%→95%之相對溼度(5%/小時)；於95%之相對溼度中3小時；95%→50%之相對溼度(10%/小時)，及於50%之相對濕度中2小時。 The dynamic moisture adsorption analysis with two cycles was carried out according to the following procedure: Samples of Form A: 2 hours at 50% relative humidity; 50% → 0% relative humidity (10%/hour); at 0% 5 hours in relative humidity; 0%→95% relative humidity (5%/hour); 3 hours in 95% relative humidity; 95%→50% relative humidity (10%/hour), and 50% 2 hours in relative humidity.

該動態濕氣吸附分析顯示兩個可逆循環中未出現明顯之質量變化(△m<0.2%)。 The dynamic moisture adsorption analysis showed no significant mass change (Δm < 0.2%) in the two reversible cycles.

將晶形A之另一樣本於室溫及85%相對濕度中儲存24小時，以供吸濕性測試。結果顯示該樣本不具吸濕性(nh)(△m=0%)。 Another sample of Form A was stored at room temperature and 85% relative humidity for 24 hours for hygroscopicity testing. The results showed that the sample was not hygroscopic (nh) (Δm = 0%).

晶形BCrystal Form B

動態濕氣吸附分析係根據下列程式，以晶形B之樣本進行：於50%之相對溼度中2小時；50%→0%之相對溼度(2.5%/小時)；於0%之相對溼度中10小時；0%→95%之相對溼度(2.5%/小時)；於95%之相對溼度中10小時；95%→50%之相對溼度(2.5%/小時)，及於50%之相對濕度中2小時。 The dynamic moisture adsorption analysis was carried out according to the following procedure: Samples of Form B: 2 hours at 50% relative humidity; 50%→0% relative humidity (2.5%/hour); 10% relative humidity Hour; 0% → 95% relative humidity (2.5% / hour); 10 hours in 95% relative humidity; 95% → 50% relative humidity (2.5% / hour), and in 50% relative humidity 2 hours.

該樣本於高於74%之相對濕度時顯示一強烈(且階段性)之吸水反應(高達約15.4%之含水量)。較低之濕度會導致水份完全流失，其於約50%之相對溼度時完全流失，即觀測到滯後現象，表示水合物之形成。 The sample exhibited a strong (and phased) water uptake reaction (up to about 15.4% water content) at a relative humidity of greater than 74%. Lower humidity results in complete loss of moisture, which is completely lost at about 50% relative humidity, ie hysteresis is observed, indicating the formation of hydrates.

為進一步闡明，對晶形B於水中進行一懸浮平衡實驗。 To further elucidate, a suspension balance experiment was performed on Form B in water.

將一晶形B之樣本於室溫懸浮數日，並以拉曼光譜測量其濕潤狀態。意外地，未發現晶形B出現轉化現象。 A sample of Form B was suspended at room temperature for several days and its wet state was measured by Raman spectroscopy. Unexpectedly, no conversion of crystal form B was observed.

於兩組對照實驗中，分別將晶形B於室溫及75.5%之相對濕度，及於室溫及97%之相對濕度中存放2星期，再以傳立葉轉換拉曼光譜分析該樣本。未觀測到轉化現象。因此重複進行動態濕氣吸附量測。數據顯示結果與第一次之動態濕氣吸附實驗相符。於進行動態濕氣吸附測量之前與之後，以傅立葉轉換拉曼光譜檢查。未觀測到轉化現象。 In the two groups of control experiments, Form B was stored at room temperature and 75.5% relative humidity, and at room temperature and 97% relative humidity for 2 weeks, and then analyzed by Fourier transform Raman spectroscopy. No conversion was observed. Therefore, the dynamic moisture adsorption measurement is repeated. The data shows that the results are consistent with the first dynamic moisture adsorption experiments. Fourier transform Raman spectroscopy was performed before and after the dynamic moisture adsorption measurement. No conversion was observed.

故進行一實驗，其晶形B之樣本係於室溫及97%之相對濕度中存放約3星期，再以傳立葉轉換拉曼光譜及熱重-傅立葉轉換紅外線連用光譜同時進行測量。傳立葉轉換拉曼光譜顯示未出現轉化現象，而熱重-傅立葉轉換紅外線連用光譜顯示約19%之含水量及約3%之二甲亞碸(二甲亞碸源自該樣本之前期準備)。結果確定顯示晶形B於高於75%之相對濕度中會吸附水分，但拉曼光譜儀未偵測到水份之吸收。 Therefore, an experiment was carried out in which the sample of Form B was stored at room temperature and 97% relative humidity for about 3 weeks, and then measured by simultaneous transfer Raman spectroscopy and thermogravimetry-Fourier transform infrared spectroscopy. The Raman spectroscopy shows that no conversion phenomenon occurs, and the thermogravimetry-Fourier transform infrared spectroscopy spectrum shows about 19% water content and about 3% dimethyl hydrazine (dimethyl hydrazine is derived from the sample preparation) . As a result, it was confirmed that the crystal form B adsorbed moisture in a relative humidity higher than 75%, but the absorption of moisture was not detected by the Raman spectrometer.

分析-於水中之溶解度 Analysis - solubility in water

水性溶解度係於再蒸餾水中從飽和溶液判定(24小時之平衡時間，室溫)。以高性能液相層析法測量其濃度，並判定該飽和溶液之酸鹼值。 The aqueous solubility was determined from the saturated solution in re-distilled water (24 hour equilibration time, room temperature). The concentration was measured by high performance liquid chromatography, and the pH value of the saturated solution was determined.

由溶解度數據中顯見鹽酸鹽之形成可改善該化合物之水性溶解度。 The aqueous solubility of the compound is improved by the formation of the hydrochloride salt as apparent from the solubility data.

分析-物理及化學安定性 Analysis - Physical and Chemical Stability

於此實驗中，將(1r,4r)-6’-氟-N,N-二甲基-4-苯基-4’,9’-二氫-3’H-螺[環己烷-1,1’-吡喃並[3,4,b]吲哚]-4-胺鹽酸鹽(於晶形A之形式)與自由鹼之物理及化學安定性進行比較。 In this experiment, (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1 , 1'-pyrano[3,4,b]indole-4-amine hydrochloride (in the form of Form A) is compared to the physical and chemical stability of the free base.

安定性測試係於兩種條件下進行。將該樣本於打開之小玻璃瓶中儲放4星期，其儲放條件為75%之相對濕度及40℃之溫度，再於閉合之小玻璃瓶中於80℃儲放1星期。以高性能液相層析法判定其純度。結果總結於表17中。 Stability testing was performed under two conditions. The sample was stored in an open vial for 4 weeks, and stored under conditions of 75% relative humidity and a temperature of 40 ° C, and stored in a closed vial at 80 ° C for 1 week. The purity was determined by high performance liquid chromatography. The results are summarized in Table 17.

該鹽酸鹽於安定性測試後並未顯示明顯之分解反應，然而該自由鹼顯示明顯之變化。 The hydrochloride did not show a significant decomposition reaction after the stability test, however the free base showed a significant change.

分析-單晶繞射 Analysis - single crystal diffraction

使用MoKα輻射(λ=0.71073 Å，Incoatec Microsource)及以配有SMART APEX-CCD之Bruker AXS D8單晶衍射儀於100 K進行測量。 Measurements were made at 100 K using MoKα radiation (λ=0.71073 Å, Incoatec Microsource) and a Bruker AXS D8 single crystal diffractometer equipped with a SMART APEX-CCD.

晶形A與D之晶體數據總結於下列表18至31 Crystal data for Forms A and D are summarized in Tables 18 to 31 below.

晶形ACrystal form A

晶形DCrystal form D

用於產生等效原子之對稱轉換： A symmetric transformation used to generate an equivalent atom:

Claims (6)

一種根據式(I)化合物之鹽酸鹽之固體晶形， 其具有位於10.6±0.2(2 Θ)、17.2±0.2(2 Θ)、18.6±0.2(2 Θ)、19.3±0.2(2 Θ)、22.2±0.2(2 Θ)、26.7±0.2(2 Θ)、及29.3±0.2(2 Θ)之X光繞射波峰(CuK α輻射)。 a solid crystal form according to the hydrochloride salt of the compound of formula (I), It has 10.6±0.2(2 Θ), 17.2±0.2(2 Θ), 18.6±0.2(2 Θ), 19.3±0.2(2 Θ), 22.2±0.2(2 Θ), 26.7±0.2(2 Θ) And an X-ray diffraction peak (CuK α radiation) of 29.3 ± 0.2 (2 Θ). 根據申請專利範圍第1項所述之固體晶形，其具有位於183±2cm-1、919±2cm-1、1001±2cm-1、1300±2cm-1、1569±2cm-1、1583±2cm-1、2992±2cm-1、3054±2cm-1與3069±2cm-1等拉曼波峰。 The solid crystal form according to claim 1 of the patent application, which has a position of 183 ± 2 cm -1 , 919 ± 2 cm -1 , 1001 ± 2 cm -1 , 1300 ± 2 cm -1 , 1569 ± 2 cm -1 , 1583 ± 2 cm - 1 , 2,892 ± 2 cm -1 , 3054 ± 2 cm -1 and 3069 ± 2 cm -1 and other Raman peaks. 根據申請專利範圍第1項或第2項所述之固體晶形，其於示差掃描熱量分析中顯示一起始溫度或波峰溫度介於262至270℃之間之吸熱事件。 The solid crystalline form according to claim 1 or 2, which exhibits an endothermic event with an onset temperature or peak temperature between 262 and 270 °C in the differential scanning calorimetry. 一種醫藥組成物，其包含根據申請專利範圍第1項或第2項所述之固體晶形。 A pharmaceutical composition comprising the solid crystalline form according to item 1 or item 2 of the patent application. 根據申請專利範圍第4項所述之醫藥組成物，其包含約0.001%以重量計至約20%以重量計之固體晶形。 The pharmaceutical composition according to claim 4, which comprises from about 0.001% by weight to about 20% by weight of the solid crystalline form. 一種獲得根據申請專利範圍第1項所述之固體晶形之方法，其包括以下步驟：a-1)將化合物(I)之鹽酸鹽由於20至40℃藉由添加莫耳過剩量之氯化氫於混合比例為40：1至10：1(v/v)之丙酮和四 氫呋喃混合物之自由鹼基之溶液或懸浮液中沉澱出；及b-1)將該固體分離；或a-2)於溫度20至40℃，將化合物(I)之鹽酸鹽以一選自二氯甲烷及二氯甲烷與甲醇混合比例為10：1至1：10之混合物之溶媒溶解；及b-2)將溶媒由該溶液中蒸發，或b-2')將化合物(I)之鹽酸鹽藉由添加選自乙酸乙酯與乙腈之沉澱劑由溶液中沉澱出；或a-3)將化合物(I)之鹽酸鹽懸浮於一選自水與選自由丙酮、四氫呋喃、二氯甲烷、N-甲基-2-吡咯啶酮及其混合物所組成群組之有機溶媒之溶媒中，並於100至40℃之溫度攪拌所得之懸浮液至少2小時；及b-3)將該固體分離。 A method for obtaining a solid crystal form according to claim 1 of the patent application, comprising the steps of: a-1) treating a hydrochloride of compound (I) by adding a molar excess of hydrogen chloride at 20 to 40 ° C; Mixing ratio of 40:1 to 10:1 (v/v) of acetone and four Precipitating in a solution or suspension of the free base of the hydrogen furan mixture; and b-1) separating the solid; or a-2) selecting the hydrochloride of the compound (I) at a temperature of 20 to 40 ° C Dissolving a solvent from a mixture of dichloromethane and dichloromethane mixed with methanol in a ratio of 10:1 to 1:10; and b-2) evaporating the solvent from the solution, or b-2') compound (I) The hydrochloride salt is precipitated from the solution by adding a precipitant selected from the group consisting of ethyl acetate and acetonitrile; or a-3) the hydrochloride of the compound (I) is suspended in a selected from the group consisting of acetone and tetrahydrofuran. a solvent in an organic solvent group consisting of dichloromethane, N-methyl-2-pyrrolidone, and a mixture thereof, and stirring the resulting suspension at a temperature of 100 to 40 ° C for at least 2 hours; and b-3) The solid was separated.
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